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Acute stressor-selective effect on total plasma homocysteine concentration in rats
Abstract
Stress produces several physiological and behavioral alterations that increase cardiovascular morbidity and mortality. Nonetheless, there is a dearth of studies that have evaluated the effects of stress on total plasma homocysteine, an important amino acid associated with cardiovascular disease. We used four distinct acute stressors in rats, i.e., swimming, restrain, novelty and cold exposure, in order to examine whether any acute effect on total plasma homocysteine concentrations would occur. Plasma corticosterone and adrenocorticotropic hormone concentrations were also measured to demonstrate the ability of the chosen manipulations to activate the hypothalamic-pituitary-adrenal (HPA) axis. Three of the four stressors activated the HPA axis and only restrain affected total plasma homocysteine concentrations (+37%, P=.006) compared with the control group. The complexity of the physiological responses to stress, the peculiarities of stress responses and the intricate regulatory systems involved in homocysteine metabolism must be taken into account in order to clarify the increasing effect of restrain (mainly a psychological stressor) on total plasma homocysteine concentrations in rats and to evaluate its meaning in human pathology.
... A realização do exercício de natação em ambas as intensidades (MFEL e 25% superior) implicou aumentos das concentrações de ACTH e corticosterona comparadas às dos animais em repouso. Esses resultados foram semelhantes aos relatados por Oliveira et al. (34) em estudos sobre o efeito agudo do exercício de natação em ratos, na atividade do eixo HHA. Em pesquisa realizada com ratos exercitados em esteira rolante, Kawashima et al. (35) encontraram resultados similares, tais como aumento nas concentrações dos hormônios corticosterona e ACTH. ...
... Os glicocorticóides são capazes de estimular a gliconeogênese pelo fígado, atuando diretamente na enzima fosfoenolpiruvato carboxiquinase (PEPCK) ou indiretamente através da sensibilidade aumentada dos hormônios responsáveis pela glicólise hepática, adrenalina e glucagon (38) . Contudo, excesso da ativação do eixo HHA e conseqüentes aumentos nas concentrações séricas de corticosterona podem levar à ruptura da homeostase e efeitos indesejáveis ao organismo (3,34) . ...
... Quando comparadas com as concentrações hormonais nas duas intensidades selecionadas (MFEL x 25% superior a esta), foram constatados aumentos mais acentuados nas concentrações de ACTH e corticosterona em intensidade 25% superior à da MFEL. Segundo Soya (34) , a atividade do eixo HHA durante exercício agudo depende da intensidade do mesmo, produzindo maior atividade em altas intensidades. Em exercícios realizados por humanos com consumo máximo de O 2 maior que 60% do VO 2 max , a secreção de ACTH e cortisol é proporcional à intensidade do exercício (40) . ...
INTRODUÇÃO: O estresse alcançado durante exercício agudo/crônico é relevante, pois altos índices de estresse podem prejudicar o bem-estar dos animais. As concentrações dos hormônios adrenocorticotrófico (ACTH) e corticosterona, bem como as concentrações de ácido ascórbico e colesterol das glândulas adrenais são importantes biomarcadores de estresse. OBJETIVO: Analisar a sensibilidade de diferentes biomarcadores de estresse em ratos durante exercício agudo de natação em diferentes intensidades. MÉTODO: Ratos (18) adaptados à natação foram submetidos a três testes de 25 minutos suportando cargas 5,0; 5,5 e 6,0% do peso corporal (PC), para obtenção da máxima fase estável de lactato (MFEL). Em seguida, os animais foram divididos em dois grupos: M (n = 9), sacrificado após 25 minutos de exercício na intensidade de MFEL e S (n = 9), sacrificado após exercício exaustivo, em intensidade 25% superior a MFEL. Para comparações, um grupo controle C (n = 10) foi sacrificado em repouso. RESULTADOS: As concentrações séricas de ACTH e corticosterona foram superiores após exercício em ambas as intensidades comparadas com o grupo controle (P < 0,05). As concentrações de ACTH e corticosterona do grupo S foram, ainda, maiores do que as do grupo M (P < 0,05). As concentrações de colesterol e ácido ascórbico na adrenal dos grupos exercitados (M e S) foram inferiores às do grupo controle (P < 0,05). Não houve diferença das concentrações de ácido ascórbico e colesterol da adrenal quando comparadas as duas intensidades de exercício (M e S) (P < 0,05). CONCLUSÃO: Todos os biomarcadores do eixo HHA apontaram alterações no nível de estresse de ratos submetidos a exercício agudo de natação; as concentrações séricas de ACTH e corticosterona mostraram-se mais sensíveis a pequenas alterações na intensidade do exercício.
... Stress has been associated with various pathological conditions. In particular, human and animal studies have provided findings on mechanisms by which stress interferes with immune (Yudkin et al. 2000), neuroendocrine (Black and Garbutt 2002) and metabolic changes (de Oliveira et al. 2004) that may increase cardiovascular risk (Manuck et al. 1995) and psychiatric illness (Agid et al. 2000). It has been reported that plasma total Hcy levels increased after acute psychological stress in human and animal studies (Stoney 1999;de Oliveira et al. 2004). ...
... In particular, human and animal studies have provided findings on mechanisms by which stress interferes with immune (Yudkin et al. 2000), neuroendocrine (Black and Garbutt 2002) and metabolic changes (de Oliveira et al. 2004) that may increase cardiovascular risk (Manuck et al. 1995) and psychiatric illness (Agid et al. 2000). It has been reported that plasma total Hcy levels increased after acute psychological stress in human and animal studies (Stoney 1999;de Oliveira et al. 2004). Our results also found that psychological stress could significantly elevate the plasma Hcy levels of rats. ...
... Usually, Hcy in rat plasma was diet-induced, i.e., by feeding high-methionine diet (Morita et al. 2001). However, some researchers reported their results after a rat was treated using different acute stress manipulations, including restraint stress, swimming and cold, and found that restraint stress was the only type of stress that altered Hcy concentrations in rats (de Souzza et al. 2006;de Oliveira et al. 2004). Their articles indicate the specific relationship between restraint stress and the increase of Hcy levels. ...
Hyperhomocysteinemia (HHcy), a pathological condition characterized by an increase in plasma concentration of total homocysteine (Hcy), is recognized as a risk factor for several diseases. The transsulfuration pathway is the main metabolic fate of Hcy utilization, which requires the activity of cystathionine β-synthase (CBS). Our results showed the development of HHcy induced by psychological stress was mainly derived from a reduction of CBS activity in the liver, which was accompanied by a significant decrease in its mRNA level. It suggested that the hepatic CBS enzyme regulated by stress at the level of transcription would have a profound effect on circulating Hcy levels. The expression of Sp3, a negative factor for cbs transcription, obviously increased in hepatocytes nuclei of stressed rats, but Sp1 was not altered. It indicated that Sp3 was the key point of variations in cbs transcription caused by stress. Meanwhile, we detected that augmented plasma Hcy concentrations correlated with glucocordicoids (GCs) over-secretion in response to stress, and CBS mRNA levels were markedly lowered in GCs-treated rat hepatocytes. Further results found that glucocorticoids receptor (GR) expression in hepatocyte nuclei of stress rats and GR nuclear translocation ratio was increased, and the same results were proved by experiments in vitro, i.e., GR nuclear translocation and Sp3 expression was remarkably increased in GCs-treated hepatocytes. Moreover, results from ChIP suggested GCs enhanced the binding of GR to the regulatory region of the Sp3 promoter. These results indicated that GCs inhibit CBS transcription by up-regulating Sp3 in psychological stress-induced HHcy.
... Stress has been associated with several pathological conditions . In particular, human and animal studies have provided findings on mechanisms by which stress interferes with immune (Yudkin et al., 2000), neuroendocrine (Muller et al., 2001; Black and Garbutt, 2002) and metabolic changes (de Oliveira et al., 2004; Setnik et al., 2004) that may increase cardiovascular risk (Blumenthal et al., 1995; Manuck et al., 1995) and psychiatric illness (Agid et al., 2000). Homocysteine is a sulphur-containing amino acid that is an intermediary in the metabolism of methionine–cysteine (Finkelstein and Martin, 2000). ...
... Yet few studies have attempted to correlate stress and homocysteine levels. Our group has previously reported that when male Wistar rats were subjected to various acute stressors, only restraint stress resulted in increased homocysteine concentrations (de Oliveira et al., 2004). While several important studies have shown that sex differences have a large influence on stress responses using behavioral paradigms (Bowman et al., 2001; Conrad et al., 2004), the role of sex differences in homocysteine concentration using classical stressors has not been examined. ...
... Among stressors, restraint resulted in a significant alteration in homocysteine plasma concentration (+ 33%, p = 0.0001). These results are in agreement with previous observations by our group using male Wistar rats, in which restraint resulted in a 37% increase in plasma homocysteine concentrations (de Oliveira et al., 2004). We can conclude, therefore, that alterations observed in plasma homocysteine concentrations induced by specific stress manipulations do not depend on gender or estrous cycle phase since they occurred in the same direction in all situations analyzed. ...
Homocysteine levels are affected by diet factors such as vitamin deficiencies, non-diet factors such as genetic disorders, and stress exposure. Hyperhomocysteinemia has been implicated in several disorders, including cardiovascular disease, depression, schizophrenia, Alzheimer's and Parkinson's disease. Since sex differences play a role both in stress responses and in susceptibility to various diseases, the objective of this study was to evaluate possible alterations in homocysteine metabolism including cysteine, folate, and vitamin B6, and oxidative stress markers in female rats exposed to different types of acute stress. Female rats were randomly distributed into eight groups according to stress manipulation (restraint, swimming, cold and control) and estrous cycle (diestrus and estrus). In general no significant differences were seen between rats in estrus and diestrus. Restraint stress was the only type of stress that altered homocysteine concentrations (+ 33% relative to controls). An increase in levels of thiobarbituric acid reactive substances (TBARS) and a decrease in total glutathione (GSHt) concentration were also observed in animals subjected to restraint and swimming stress, suggesting the possibility of oxidative damage. Thus, both the homocysteine results and the oxidative stress data indicated that restraint stress was the most powerful stress manipulation in female rats, as previously observed in male rats.These findings indicate that hormonal and gonadal differences do not interfere with stress responses related to homocysteine metabolism and suggest that putative gender-related differences in homocysteine responses are probably not involved in the differential prevalence of some diseases in human males and females.
... Aside from the factors mentioned above, Stoney et al.. demonstrated that acute psychological stress could induce rapid and significant elevations in the plasma total Hcy concentration in a sample of women between 40 and 63 years of age [12]. Oliveira et al.. found that with exposure to restraint stress, a model of psychological stress in rats, the total plasma Hcy concentration increased significantly [13]. Our previous results supported this finding. ...
... Before the initiation of the experiment and every two weeks for 8 weeks, blood was collected from the medial angle of the rat eye into precooled plastic vials containing 0.2 ml of an EDTANa 2 solution (60 mg/ml) and centrifuged at 900 g for 20 min at 4uC. The plasma was extracted, transferred to plastic tubes and stored at 280uC until the Hcy assays were performed [13,26]. ...
Background
Although the accumulation of homocysteine (Hcy) has been implicated in the pathogenesis of depression, whether Hcy is directly involved and acts as the primary cause of depressive symptoms remains unclear. The present study was designed to clarify whether increased Hcy plays an important role in stress-induced depression.
Results
We employed the chronic unpredictable mild stress model (CUMS) of depression for 8 weeks to observe changes in the plasma Hcy level in the development of depression. The results showed that Wistar rats exposed to a series of mild, unpredictable stressors for 4 weeks displayed depression-like symptoms such as anhedonia (decreased sucrose preferences) and a decreased 5-Hydroxy Tryptophan (5-HT) concentration in the hippocampus. At the end of 8 weeks, the plasma Hcy level increased in the CUMS rats. The anti-depressant sertraline could decrease the plasma Hcy level and improve the depression-like symptoms in the CUMS rats. RhBHMT, an Hcy metabolic enzyme, could decrease the plasma Hcy level significantly, although it could not improve the depressive symptoms in the CUMS rats.
Conclusions
The results obtained from the experiments did not support the hypothesis that the increased Hcy concentration mediated the provocation of depression in CUMS rats, and the findings suggested that the increased Hcy concentration in the plasma might be the result of stress-induced depression.
... A significant association between elevated plasma homocysteine levels and depression has been reported by a number of researchers, which predicted that more than half of those with depression will experience elevated plasma homocysteine levels (Bottiglieri et al., 2000;Reif et al., 2003;Tiemeier et al., 2002). In addition, the association between homocysteine and stress in human and animal models has been reported (Kang et al., 2005;de Oliveira et al., 2004;de Souza et al., 2006). ...
Background and objective:
Patients with panic disorder (PD) suffer from elevated oxidative stress as a consequence of serotonin metabolism disorder. These patients have elevated serotonin concentration and catabolism of serotonin via monoamine oxidase. The aim of the present study was to evaluate serum homocysteine concentration and its relationship with oxidative stress level in PD patients, regarding homocysteine as a diagnostic biomarker of heart disease.
Materials & method:
Sixty patients with PD according to the DSM-5 diagnostic criteria for a panic attack and 60 healthy individuals were included in the present study. Peripheral venous blood samples were taken from patients. Erythrocytes and serum were separated from blood, and RBC hemolysates were prepared to investigate oxidative stress indices including glutathione and glutathione peroxidase. Serum homocysteine and carbonyl groups concentrations were measured in all samples. Data were analyzed using ANOVA, and p < .05 was considered significant.
Results:
Results showed that serum carbonyl groups concentration was significantly higher in patients with PD than in healthy individuals (p < .001). The results also indicated decreased serum glutathione concentration and glutathione peroxidase activity in patients (p < .003). In addition, elevated homocysteine concentration in PD patients serum was observed during the present study (p < .003).
Conclusion:
Our findings support that patients with PD experience higher levels of oxidative stress, due to impaired serotonin metabolism, which is related to the prognosis of heart disease in these patients.
... It is worth noting that psychological stress was significantly related to higher levels of plasma homocysteine [7]. Rodents studies show that plasma Homocysteine significantly increases just after restrained stress [8,9]. And both chronic [10] or acute [11,12] psychological stress could result in increased plasma homocysteine levels in human studies. ...
... Circulating corticosterone is a sensitive index for evaluating the stress intensity and correlates with stress intensities at low and middle levels (Armario et al., 1986;De Boer et al., 1990). As proof of handling stress for the mild stressor, the handling stress-induced increase in circulating corticosterone (2-4 fold) is equivalent to the increase by novelty stress (2-5 fold), but smaller than the increases by tail pinch (5 fold), cold exposure (6 fold), restraint (7-32 fold) and water immersion (9-14 fold) stresses (Armario et al., 1986;De Boer et al., 1990;Balcombe et al., 2004;de Oliveira et al., 2004;Butts et al., 2011). ...
Background:
Cortical dopamine and noradrenaline are involved in the stress response. Citalopram, a selective serotonin reuptake inhibitor, has direct and indirect effects on the serotonergic system. Furthermore, long-term treatment with citalopram affects the dopamine and noradrenaline systems, which could contribute to the therapeutic action of antidepressants.
Methods:
The effects of long-term treatment with citalopram on the responses of the dopamine and noradrenaline systems in the rat prefrontal cortex to acute handling stress were evaluated using in vivo microdialysis.
Results:
Acute handling stress increased dopamine and noradrenaline levels in the prefrontal cortex. The dopamine and noradrenaline responses were suppressed by local infusion of a 5-HT1A receptor agonist, 7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol;hydrobromide, into the prefrontal cortex. The dopamine response was abolished by long-term treatment with citalopram, and the abolished dopamine response was reversed by local infusion of a 5-HT1A receptor antagonist, (Z)-but-2-enedioic acid;N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexanecarboxamide into the prefrontal cortex. On the other hand, long-term treatment with citalopram reduced the basal noradrenaline levels (approximately 40% of the controls), but not the basal dopamine levels. The noradrenaline response was maintained despite the low basal noradrenaline levels. Signaling from the 5-HT1A receptors and α2-adrenoceptors was not involved in the decrease in the basal noradrenaline levels but partially affected the noradrenaline response.
Conclusions:
Chronic citalopram treatment differentially suppresses the dopamine and noradrenaline systems in the prefrontal cortex, and the dopamine stress response was preferentially controlled by upregulating 5-HT1A receptor signaling. Our findings provide insight into how antidepressants modulate the dopamine and noradrenaline systems to overcome acute stress.
... and B12), several factors, including hormones, redox state as well as immune mediators, are involved in the complex regulation of Hcy metabolism (House et al., 1999; Graham and O'Callaghan, 2002; Vitvitsky et al., 2003; Tobena et al., 1996). Stress is one of the factors that could be responsible for changes in Hcy levels in schizophrenic patients. de Oliveira et al. (2004) investigated the effects of stress on total plasma Hcy using four distinct acute stressors in rats: swimming, restrain, novelty and cold exposure. Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis was seen after all stress manipulations except novelty. Plasma Hcy changes occurred in a stressor-specific manner and restr ...
High levels of homocysteine (Hcy) were suggested to contribute to the pathogenesis of schizophrenia. Recent investigations have shown that treatment with folic acid, vitamin B-12 and pyridoxine are effective in reducing Hcy levels while concomitantly reducing the score of positive and negative symptoms in schizophrenic patients. In addition to the availability of nutrients (mainly folate, vitamins B6 and B12), plasma Hcy concentrations are dependent on complex metabolic regulation that could be disrupted in schizophrenia.
... Plasma corticosterone and adrenocorticotropic hormone concentrations were also measured to demonstrate the ability of the chosen manipulations to activate the hypothalamic-pituitary-adrenal (HPA) axis. Three of the four stressors activated the HPA axis and only restrain increased tHcy concentrations [5]. Stoney et al.'s study was to test if acute psychological stress could induce elevations in plasma Hcy concentrations. ...
... As PTSD is likely to add to chronic stress load, the study's findings point to a potential association between stress and higher Hcy plasma levels. In terms of acute stress reactivity, studies in rodents show increases in plasma Hcy immediately after restrained stress (de Oliveira et al., 2004;de Souza et al., 2006). However, human studies investigating Hcy reactivity to acute stress are rare and results are contradictory. ...
Background:
The incidence and prevalence of cardiovascular disease (CVD) increases with age. Some evidence suggests that mental stress may increase plasma homocysteine (Hcy), an amino acid relating to CVD. However, none of these studies assessed age effects on Hcy stress reactivity, nor did they control for age. The objective of this study was (a) to investigate whether Hcy reactivity to psychosocial stress differs between younger and middle-aged to older men and (b) to study whether psychosocial stress induces Hcy increases independent of age.
Methods:
Twenty eight younger (20-30 years) and 22 middle-aged to older (47-65 years) apparently healthy men underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. Blood samples for Hcy measurements were obtained immediately before and after, as well as 10 and 20min after stress. Moreover, salivary cortisol was repeatedly measured to test the effectiveness of the stress task in triggering a neuroendocrine stress response.
Results:
Hcy reactivity to stress differed between age groups (F(1.4, 60.7)=5.41, p=.014). While the older group displayed an increase in the Hcy response to stress (F(2.5, 39.8)=3.86, p=.022), Hcy levels in the younger group did not change (p=.27). Psychosocial stress per se did not change Hcy levels independent of age (p=.53).
Conclusions:
Our findings suggest that psychosocial stress does not evoke an Hcy response per se, but only in interaction with age pointing to a mechanism by which mental stress may increase CVD risk in older individuals.
... However, it has been proved that restraint stress has significant influence on the adrenal cortex and then lead to vasculature and metabolism system damage in rats [37][38][39]. Furthermore, de Souza et al. and de Oliveira et al. reported their results after a rat was treated using different stress manipulations, including restraint stress, swimming and cold, and found that not all stress manipulations could increase homocysteine concentrations in rat plasma, and restraint stress was the only type of stress that altered homocysteine concentrations in rat [40,41]. So, their papers indicate the specific relationship between restraint stress and the increase of homocysteine levels. ...
Stress is a risk factor for many diseases. In this study, we used fluorescence difference gel electrophoresis combined MALDI-TOF/TOF and 1H-NMR to monitor the intracellular processes in rat liver at proteomic and metabonomic levels when a rat was treated with restraint stress for 8 weeks. Dynamic changes in 42 proteins and 32 chemical groups were monitored and identified. These proteins and chemical groups were implicated in glycolysis, the tricarboxylic acid cycle, fatty acid oxidation, and the urea cycle. To verify the DIGE result, three proteins including DJ-1, Blvrb and AdoHycase were validated by Western blot. Furthermore, some metabolites related to diseases such as lactate, fatty acid, glucose and homocysteine, were observed to be increasing during 8 weeks of restraint stress. Our data indicated that subclinical hepatic injury occurs during restraint stress, including inhibition of glycolysis and gluconeogenesis in the liver, and dysfunction of fatty acid beta-oxidation. The results suggest a comprehensive map that addresses how functional proteins act on metabolites to produce energy and process materials in rat liver as it responds to restraint stress. Further functional study on these dynamic change proteins and metabolites may lead to better understanding of the mechanisms of stress-induced diseases.
... Both ends of the cylinders were closed with ventilation sliding doors. Animals were sacrificed immediately after the end of the immobilization period [22] . ...
Brain enkephalin and oxytocin are anxiolytic agents involved in the response mechanism to stress. Degrading enzymes such as enkephalinase and oxytocinase could also be associated with this response. The effect of acute immobilization stress on enkephalinase and oxytocinase activities was determined in the soluble and membrane fractions of the medial prefrontal cortex, hippocampus and amygdala using alanyl- and leucyl-beta-naphthylamide as substrates, the latter in the presence and absence of 20 mM L-methionine. No change in aminopeptidase activities was observed in the prefrontal cortex of stressed rats. In contrast, enkephalinase activity decreased in the soluble fraction of the hippocampus but increased in the membrane fraction. In the amygdala, soluble oxytocinase and membrane enkephalinase activities decreased in stressed animals. These results show that acute immobilization stress affects differentially enkephalinase and oxytocinase activities depending on the fraction and brain region analyzed. A reduction in the activity of soluble enkephalinase in the hippocampus and soluble oxytocinase as well as membrane enkephalinase in the amygdala may suggest higher availability/longer action of enkephalin and oxytocin at these locations. This may explain the relative importance of these enzymatic activities in the anxiolytic properties proposed for enkephalins and oxytocin in the hippocampus and amygdala during stress conditions. This interpretation is not applicable to membrane enkephalinase activity in the hippocampus. However, alanyl-beta-naphthylamide hydrolyzing activity not only measures enkephalinase activity, it also reflects the angiotensinase-induced metabolism of angiotensin III to angiotensin IV. Therefore, our results may also mirror an increase in the formation of Ang IV in hippocampus and a decrease in the amygdala in acute stress. In conclusion, aminopeptidase activities in the hippocampus and amygdala may affect enkephalin, oxytocin and angiotensin III metabolism during acute immobilization stress and therefore be involved in the anxiolytic response.
... Comprehensive investigations are needed to resolve the effects of sleep deprivation and hypoxia on homocysteine metabolism. The homocysteine results are probably not related to stress since de Oliveira et al. (2004) showed that acute stress either increased total homocysteine concentrations (1 h of immobilization), or failed to affect homocysteine (forced swimming, restraint and exposure to cold). One of the stresses in the hypoxia technique is the noise produced by the air flushed in the hypoxia chamber, but acoustic stress does not seem to induce long-term cardiovascular alterations in rats (Bao et al., 1999). ...
Since studies suggest that both hypoxia and sleep fragmentation are related to cardiovascular alterations induced by obstructive sleep apnea, the present study was designed to evaluate the effects of hypoxia, sleep deprivation, and their combination on biochemical blood parameters in rats. In subchronic experiments (4 days), rats were exposed to intermittent hypoxia (IH) during the light period (2min room air-2min 10% O(2) for 12h/day) and/or paradoxical sleep deprivation (PSD, 24h/day). Consequences of chronic intermittent hypoxia (CIH) exposure were examined after 21 consecutive days of hypoxia protocol from 10:00 to 16:00 followed by a sleep restriction (SR) period of 18h (16:00-10:00). Rats were randomly assigned to seven treatment groups: (1) control (2) IH (3) PSD (4) IH-PSD (5) SR (6) CIH and (7) CIH-SR. PSD reduced triglycerides and very low-density lipoprotein (VLDL) cholesterol concentrations and increased total cholesterol and high-density lipoprotein (HDL) cholesterol. IH did not alter any of these parameters. The combination of IH-PSD did not modify the values of total cholesterol and HDL compared to control group. In the chronic experiment, the animals exposed to CIH displayed a reduction of Vitamin B(6) and an increase of triglycerides and VLDL. Our findings show a duration-dependent effect of hypoxia on triglycerides. Rats in the SR and CIH-SR groups showed a diminished concentration of triglycerides and VLDL. SR rats showed a reduction in the concentration of homocysteine but the animals in the CIH-SR treatment condition did not display any alterations in this parameter. In this latter group, an augmentation of cysteine concentration was observed. These results suggest that sleep deprivation and hypoxia modify biochemical blood parameters in distinct ways.
... The results of animals submitted to swimming exercise were similar to those reported by de Oliveira et al. (2004) in studies on the acute effect of the swimming exercise in rats, with significant increases on the corticosterone and ACTH hormone concentrations. In contrast, Kawashima et al. (2004) in research performed with treadmill-exercised rats found significant increase in both corticosterone and ACTH hormones concentrations. ...
The objective of the present work was to compare stress biomarkers (serum ACTH and corticosterone hormones) during known intensity swimming and treadmill running exercises performed by rats. Adult Wistar rats (n=41) weighing 320-400 g at the beginning and 420-500 g at the end of the experiment, previously adapted to exercise and with Maximal Lactate Steady State (MLSS) already determined were used. The animals were divided into the following subgroups: (1) sacrificed shortly after session of 25 min of exercise (swimming or treadmill) at the MLSS intensity or (2) sacrificed after exhaustive exercise (swimming or treadmill) at intensity 25% higher than MLSS. For comparison, a control group C was sacrificed at rest. Two-way ANOVA was used to identify differences in the stress parameters (P<0.05). At both exercise intensities serum ACTH concentrations were significantly higher for the swimming group compared to running and control groups, while serum corticosterone concentrations in swimming and running groups were significantly higher than in the control group. The differences were more pronounced at the higher intensity (25% higher than MLSS). The swimming group showed higher concentrations for both hormones in relation to the running group. Only acute swimming exercise induced activity of the hypothalamic-pituitary-adrenal axis responses expected to stress: elevations in the serum ACTH and corticosterone concentrations.
Inflammatory diseases comprise a broad and heterogeneous range of disorders of different origins. Immune-mediated inflammatory diseases characterized by chronic systemic inflammation are caused by immune system disorders that can affect different organs. Autoimmune diseases are of uncertain etiology, though genetic and environmental factors are known to play a role in their etiopathogenesis. They develop when intrinsic immune system damage results in a loss of self-tolerance, giving rise to abnormal reactions against the host tissues that persist over time.
High homocysteine (Hcy) concentration in serum has been associated to stress and inflammation in humans, but this association has not been studied in saliva in any animal species. The purpose of this research was to study salivary Hcy levels in pigs under stressful and inflammatory conditions. A commercially available enzyme-linked immunosorbent assay specific for Hcy determination in pigs was adapted and validated in saliva, yielding reproducible and accurate results. Hcy was measured in paired serum-saliva samples and no correlation was observed between serum and salivary Hcy. Salivary Hcy was measured in two experimental models of stress induction in pigs: restraint with a nasal snare and isolation. Homocysteine concentration and the homocysteine to total protein (Hcy/TP) ratio significantly increased 15 min after restraining and decreased after some days of isolation. Significant correlation was observed between Hcy and chromogranin A. After an experimentally induced inflammation by subcutaneous turpentine injection, salivary Hcy increased only 3 h after turpentine administration; however, the Hcy/TP ratio did not show any change. No correlation was found between salivary Hcy and serum C-reactive protein. In conclusion, salivary Hcy concentration increased when pigs were restrained with a nasal snare or stressed by isolation, probably reflecting an increase in the sympathetic activity. On the other hand, Hcy increased after an experimental inflammation induced by turpentine administration but in this case probably reflects an increase in total protein production in saliva.
Early-life stress (ES) impairs cognition later in life. Because ES prevention is problematic, intervention is needed, yet the mechanisms that underlie ES remain largely unknown. So far, the role of early nutrition in brain programming has been largely ignored. Here, we demonstrate that essential 1-carbon metabolism-associated micronutrients (1-CMAMs; i.e., methionine and B vitamins) early in life are crucial in programming later cognition by ES. ES was induced in male C57Bl/6 mice from postnatal d (P)2-9. 1-CMAM levels were measured centrally and peripherally by using liquid chromatography-mass spectroscopy. Next, we supplemented the maternal diet with 1-CMAM only during the ES period and studied cognitive, neuroendocrine, neurogenic, transcriptional, and epigenetic changes in adult offspring. We demonstrate that ES specifically reduces methionine in offspring plasma and brain. Of note, dietary 1-CMAM enrichment during P2-9 restored methionine levels and rescued ES-induced adult cognitive impairments. Beneficial effects of this early dietary enrichment were associated with prevention of the ES-induced rise in corticosterone and adrenal gland hypertrophy did not involve changes in maternal care, hippocampal volume, neurogenesis, or global/Nr3c1-specific DNA methylation. In conclusion, nutrition is important in brain programming by ES. A short, early supplementation with essential micronutrients can already prevent lasting effects of ES. This concept opens new avenues for nutritional intervention.-Naninck, E. F. G., Oosterink, J. E., Yam, K.-Y., de Vries, L. P., Schierbeek, H., van Goudoever, J. B., Verkaik-Schakel, R.-N., Plantinga, J. A., Plosch, T., Lucassen, P. J., Korosi, A. Early micronutrient supplementation protects against early stress-induced cognitive impairments.
Aim: Mental situations are known to induce oxidative stress in individuals subjected to intense psychological conditions. We investigated the serum Antioxidant Vitamins, Retinol (vitamin A), alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C), Malondialdehyde (MDA), alanine transaminase (ALT) and aspartate transaminase (AST) levels of Professional Football Managers during Derby Matches in the 2009-2010 season of the 2nd division of the Turkish professional soccer league in the two neighboring provinces matches (Elazig Football Club-Malatya Football Club), which is described as a derby match. Method: The serum samples of twenty club managers of Elazig Football Club were evaluated for study. Changes in biochemical indices of oxidative damage and enzyme markers of stress were examined during a competitive football season. The main findings of the present study were that the serum Malondialdehyde and blood ALT and AST levels of this group of managers displayed differences at home and displacement. Results: The participants in the two matches went through a period of heavy mental stress. In mean average values and statistical results, they showed changes in their serum MDA, ALT and AST concentrations. Conclusion: In conclusion, the excessive excitement and stress can be effective on professional football manager during derby matches. The results of this study indicated that match stress affects the managers physiologically.
Betaine plays important roles that include acting as a methyl donor and converting homocysteine (Hcy) to methionine. Elevated plasma Hcy levels are known as hyperhomocysteinemia (HHcy) and contribute to impairments of learning and memory. Although it is commonly known that betaine plays an important role in Hcy metabolism, the effects of betaine on Hcy-induced memory impairment have not been investigated. Previously, we demonstrated the beneficial effects of betaine on acute stress and lipopolysaccharide-induced memory impairment. In the present study, we investigated whether betaine ameliorates Hcy-induced memory impairment and the underlying mechanisms of this putative effect. Mice were treated with Hcy (0.162mg/kg, s.c.) twice a day for nine days, and betaine (25mg/kg, s.c.) was administered 30min before the Hcy injections. The memory functions were evaluated using a spontaneous alternation performance test (Y-maze) at seven days and a step-down type passive avoidance test (SD) at nine and 10 days after Hcy injection. We found that betaine suppressed the memory impairment induced by repeated Hcy injections. However, the blood concentrations of Hcy were significantly increased in the Hcy-treated mice immediately after the passive avoidance test, and betaine did not prevent this increase. Furthermore, Hcy induces redox stress in part by activating matrix metalloproteinase-9 (MMP-9), which leads to BBB dysfunction. Therefore, we tested whether betaine affected MMP-9 activity. Interestingly, treatment with betaine significantly inhibited Hcy-induced MMP-9 activity in the frontal cortex but not in the hippocampus after acute Hcy injection. These results suggest that the changes in MMP-9 activity after betaine treatment might have been partially responsible for the amelioration of the memory deficits and that MMP-9 might be a candidate therapeutic target for HHcy.
Copyright © 2015. Published by Elsevier B.V.
Abstract
Aims
The specific aim of this review was to compile the first systematic review of systematic reviews and meta-analyses from a range of studies that evaluates the evidence that elevated homocysteine may be a risk factor for CVD.
Data synthesis
379 entries were identified by initial screening using set criteria revealing eleven meta-analyses, one systematic review, two systematic reviews/meta-analyses and ten other studies, between 1994 and 2013.These studies compared homocysteine levels and its relationship with twelve different types of CVD chronic conditions. Final methodological quality assessment was conducted independently using the instrument AMSTAR for the systematic reviews and meta-analyses. The remaining studies were assessed using data extraction tools from JBI QARI, Appendix 2 & 4 packages.
Conclusions
From the selected studies, 82.8% of the CVD conditions demonstrated that epidemiologic and clinical data strongly indicated that elevated homocysteine levels is a risk factor for primary CVD. 71.4% of the CVD conditions demonstrated that plasma tHcy can be employed as an independent biomarker. Despite 46.2% of the CVD conditions finding that reducing plasma tHcy lowers the risk of many CVD events, it remains unclear whether the reduction in plasma tHcy will reduce the risk of some CVD events; it is therefore considered prudent to take precautionary measures to aim for normal levels of homocysteine to avoid the risk of developing or exacerbating CVD. Moreover, it was shown that levels of homocysteine can be profoundly affected by diet, supplementation and lifestyle.
The present study will help to clarify the present scientific understanding of this subject.
It has been suggested that an elevated serum or plasma homocysteine level may be a risk factor for neuropsychiatric conditions such as Alzheimer's disease, schizophrenia, and depression. Because depression is closely related to anxiety disorders, and because it has been suggested that stress may be associated with an elevated homocysteine level, we studied whether serum homocysteine levels are elevated in patients with posttraumatic stress disorder (PTSD). Total serum homocysteine levels in 28 male patients with PTSD were compared to those of 223 healthy controls. The effect of PTSD on the serum homocysteine level was significant (F=42.96, P<.0001). In a regression model for the PTSD patients, the duration of PTSD was found to predict serum homocysteine levels (t=2.228, P=.035). Our results suggest that elevated levels of homocysteine in male patients with PTSD may be related to pathophysiological aspects associated with the chronicity of this disorder. Depression and Anxiety, 2008. © 2007 Wiley-Liss, Inc.
Bran cereals are known to contain substantial concentrations of important nutrients, bioactive compounds, fiber, minerals, proteins, lipids, and vitamins. The vitamins present in rice bran include those of the B complex (B(1) and B(3)), which affect the central nervous system (natural antidepressant and tranquilizer effects) acting in schizophrenia, neuralgia, and fatigue. The elevated plus maze (EPM) test is a model widely used for the study of anxiety in animals. The forced swimming (FS) test is the model used most often for evaluating the antidepressant activity in animal models in pharmacology. This study examined the behavior of 32 male Wistar rats, 21 days old, in the FS and EPM tests after treatment with strawberry- or chocolate-flavored rice bran drink for 28 days. The concentration of adrenocorticotropic hormone in the plasma of the animals was determined at the beginning and end of treatment. The values found (<1.0 mg/dL) showed no significant difference between the test and control groups in the periods analyzed. In the EPM, ingesting the chocolate-flavored drink showed an anxiogenic trend in the rats, and the strawberry-flavored rice bran drink led to an anxiolytic profile, although the difference was not statistically significant (P > .05). In the FS test, the duration of immobility of rats in groups consuming rice bran drinks was higher than in the control group, but without a statistically significant difference (P > .05). However, this result may indicate a tendency toward an effect on the central nervous system of the animals after the ingestion of the rice bran beverage.
To evaluate the influence of early life environments on basal and cold stress-induced sleep patterns in rats.
The design was a 3 (Groups [control, early handling, maternal separation]) x 2 (Situations [basal, poststress]) x 11 (Time-blocks) factorial design. From postnatal days 2 to 14, whole litters were either submitted to early handling (15 minutes per day away from the mother) or maternal separation (180 minutes per day away from the mother). At 75 to 90 days of age, sleep was recorded for 22 hours (beginning at 9:00 AM) before and after 1 hour of cold stress (4 degrees C).
Wistar male rats (n = 7-10 animals per group).
Sleep was analyzed in blocks of 2 hours, in 30-second epochs, separately in the daytime and nighttime sleep recordings. Maternally separated rats exhibited more paradoxical sleep at baseline, compared to both control and early-handled rats. In the first 2 hours following the end of cold stress, all groups showed a decrease in paradoxical sleep, whereas slow-wave sleep was reduced only in the control group. The highest corticosterone plasma concentration was observed immediately after stress. Sleep rebound after stress was equally manifested in all groups in the dark part of the light-dark cycle.
Maternal separation during early infancy resulted in permanent changes of the sleep architecture reflected by augmented time spent in paradoxical sleep. Although these findings were not expected in light of the literature, they emphasize the importance of the early familiar environment on future behavior of rats.
We have previously reported that acute immobilization stress induces Fos protein. Fos protein is generally used as a marker for neuronal activity and has been linked to phosphorylation of extracellular signal-regulated protein kinase 1/2 (pERK1/2), in the hypothalamic paraventricular nucleus (PVN). Biting behavior during the period of stress reduced the expression of Fos protein. The present immunohistochemical study was designed to determine whether acute immobilization stress induces pERK1/2 in the PVN, and whether the stress-induced pERK1/2 was attenuated by simultaneous biting behavior. Acute immobilization stress, in increments of up to 15min, produced detectable amounts of pERK1/2 that were proportional to the interval of stress. Biting during the acute immobilization stress significantly reduced the amount of detectable pERK1/2. These results suggest that biting activity during acute stress inhibits pERK1/2 in this region of the brain. It is feasible that the neuronal cellular response to acute stress is regulated, in some part, by inhibition of pERK1/2 by biting.
Activation of the hypothalamus-pituitary-adrenal axis plays a major role in the suppression of the immune system. We have investigated the effects of repetitive stress on Wistar rats infected with the Y strain of Trypanosoma cruzi and a control group that underwent stressor stimuli by exposure to ether vapor for one minute twice a day. Repetitive stress resulted in an elevated number of circulating parasites accompanies by deep tissue disorganization, and cardiac histopathological alterations. The infected and stressed group displayed a decrease in body weight, and an increased parasite burden in heart tissue, and adrenal glands. Histological analysis of the heart also showed a moderate to severe diffused mononuclear inflammatory process. These results suggest that repetitive stress could be considered an important factor during development of experimental Chagas' disease, enhancing pathogenesis through disturbance of the host's immune system.
The effect of chronic water deprivation on metabolic rate and long-trace taste-aversion conditioning was examined in Wistar-derived rats. Subjects were either maintained on a water deprivation regimen or allowed free access to water for a seven-week period prior to conditioning. At conditioning, rats were presented a saccharin CS followed 0-, 45-, 90-, or 180-min later by an i.p. injection of LiCl. Additionally, pseudo-conditioned groups were presented the CS followed immediately by an injection of physiological saline. Heightened oxygen consumption in deprived subjects suggested that chronic water deprivation increased metabolic rate. While no differences in the amount of saccharin intake were observed at conditioning, percent preference for saccharin scores during a 24-h two-bottle water/saccharin test revealed that non-chronically deprived rats supported conditioning at longer CS-US intervals than did chronically water-deprived rats. Results are interpreted in terms of a time-contraction effect stemming from an alteration of an internal metabolic count-down timer.
The purpose of this study was to determine the correspondence of mental stress-induced ischemia in the laboratory with ambulatory ischemia and to assess the relationship between hemodynamic responses to mental stress and the occurrence of ischemia. Although exercise testing is usually used to elicit myocardial ischemia, ischemia during daily life usually occurs at relatively low heart rates and in the absence of strenuous physical exercise. Mental stress has been shown to trigger ischemic events in the laboratory at lower heart rates but at blood pressures comparable to exercise. We therefore compared the extent to which mental stress and exercise testing identify patients who develop ischemia out of hospital.
One hundred thirty-two patients with documented coronary disease and recent evidence of exercise-induced myocardial ischemia underwent 48-hour ambulatory monitoring and radionuclide ventriculography during exercise and mental stress testing. Patients who displayed mental stress-induced ischemia in the laboratory were more likely to exhibit ischemia during daily life (P < .021). Furthermore, patients who exhibited ischemia during ambulatory monitoring displayed larger diastolic blood pressure (P < .006), heart rate (P < .039), and rate-pressure product responses (P < .018) during mental stress.
Among patients with prior positive exercise stress tests, mental stress-induced ischemia, defined by new wall motion abnormalities, predicts daily ischemia independent of exercise-induced ischemia. Exaggerated hemodynamic responses during mental stress testing also identify individuals who are more likely to exhibit myocardial ischemia during daily life and mental stress.
The regulation of expression of the gamma-S-adenosyl-L-methionine (AdoMet) synthetase gene was investigated in T-cells during G0/G1 transition, as well as throughout the G1 phase. Stimulation of G0 T-lymphocytes with concanavalin A induces AdoMet synthetase gene expression, starting 8 h after stimulation. Interleukin-2 (IL-2) stimulates the induction of this gene expression and AdoMet synthetase activity in G1 lymphoblasts, in part by an increase in the transcription rate of the gene. Phorbol esters, which also stimulate the proliferation of G1 lymphoblasts, show a similar kinetics of AdoMet synthetase mRNA induction. In contrast, the mRNA levels of the S-adenosyl-L-homocysteine hydrolase, another enzyme of the methionine cycle, remain unchanged upon IL-2 or phorbol 12,13-dibutyrate treatment. Dexamethasone and 8Br-cAMP, both inhibitors of lymphocyte proliferation, are able to block the expression of the AdoMet synthetase gene and, consequently, AdoMet synthetase activity. Together these findings indicate that the AdoMet synthetase gene is subject to cell-cycle regulation in T-lymphocytes.
Cocaine or air jet stress evokes pressor responses due to either a large increase in systemic vascular resistance (vascular responders) or small increases in both cardiac output and vascular resistance (mixed responders) in conscious rats. Repeated cocaine administration results in elevated arterial pressure in vascular responders but not in mixed responders. The present study examined the hypothesis that the pattern of cardiovascular responses to an unconditioned stimulus (UCS; air jet) is related to responses to a conditioned stimulus (CS; tone followed by brief foot shock) in individual rats. Our data demonstrate that presentation of the UCS produced variable cardiac output responses that correlated with responses to the CS (n = 60). We also determined whether individual cardiovascular response patterns to acute stress correlated with predisposition to a sustained stress-induced elevation in arterial pressure. Rats were exposed to three different stressors presented one per day successively for 4 wk and during a poststress period of 3 wk while arterial pressure was recorded periodically. Mean arterial pressure was elevated in all rats during chronic stress but, during the poststress period, remained at significantly higher levels in vascular responders but not mixed responders. Therefore, we conclude that acute behavioral stress to a conditioned stimulus elicits variable hemodynamic responses that predict the predisposition to a sustained stress-induced elevation in arterial pressure.
Despite the fact that many research articles have been written about stress and stress-related diseases, no scientifically accepted definition of stress exists. Selye introduced and popularized stress as a medical and scientific idea. He did not deny the existence of stressor-specific response patterns; however, he emphasized that such responses did not constitute stress, only the shared nonspecific component. In this review we focus mainly on the similarities and differences between the neuroendocrine responses (especially the sympathoadrenal and the sympathoneuronal systems and the hypothalamo-pituitary-adrenocortical axis) among various stressors and a strategy for testing Selye's doctrine of nonspecificity. In our experiments, we used five different stressors: immobilization, hemorrhage, cold exposure, pain, or hypoglycemia. With the exception of immobilization stress, these stressors also differed in their intensities. Our results showed marked heterogeneity of neuroendocrine responses to various stressors and that each stressor has a neurochemical "signature." By examining changes of Fos immunoreactivity in various brain regions upon exposure to different stressors, we also attempted to map central stressor-specific neuroendocrine pathways. We believe the existence of stressor-specific pathways and circuits is a clear step forward in the study of the pathogenesis of stress-related disorders and their proper treatment. Finally, we define stress as a state of threatened homeostasis (physical or perceived treat to homeostasis). During stress, an adaptive compensatory specific response of the organism is activated to sustain homeostasis. The adaptive response reflects the activation of specific central circuits and is genetically and constitutionally programmed and constantly modulated by environmental factors.
An elevated plasma level of homocysteine is a risk factor for the development of cardiovascular disease. The purpose of this
study was to investigate the effect of glucagon on homocysteine metabolism in the rat. Male Sprague-Dawley rats were treated
with 4 mg/kg/day (3 injections per day) glucagon for 2 days while control rats received vehicle injections. Glucagon treatment
resulted in a 30% decrease in total plasma homocysteine and increased hepatic activities of glycine N-methyltransferase, cystathionine β-synthase, and cystathionine γ-lyase. Enzyme activities of the remethylation pathway were
unaffected. The 90% elevation in activity of cystathionine β-synthase was accompanied by a 2-fold increase in its mRNA level.
Hepatocytes prepared from glucagon-injected rats exported less homocysteine, when incubated with methionine, than did hepatocytes
of saline-treated rats. Flux through cystathionine β-synthase was increased 5-fold in hepatocytes isolated from glucagon-treated
rats as determined by production of14CO2 and α-[1-14C]ketobutyrate froml-[1-14C]methionine. Methionine transport was elevated 2-fold in hepatocytes isolated from glucagon-treated rats resulting in increased
hepatic methionine levels. Hepatic concentrations of S-adenosylmethionine andS-adenosylhomocysteine, allosteric activators of cystathionine β-synthase, were also increased following glucagon treatment.
These results indicate that glucagon can regulate plasma homocysteine through its effects on the hepatic transsulfuration
pathway.
The endothelins (ET-1, 2 and 3) constitute a family of 21 amino acid peptides with potent biological activities. ET-1 is one of the most potent endogenous vasoconstrictors so far identified and its increased concentration in plasma appears to be closely related to the pathogenesis of arterial hypertension as well as to obstructive sleep apnea (OSA). OSA patients exhibit repetitive episodes of apnea and hypopnea that result in hypoxia and consecutive arousals. These patients are chronically sleep deprived, which may aggravate the hypertensive features, since literature data show that sleep deprivation results in hypertension both in humans and in animals. Based on the reported relationship between ET-1, hypertension and sleep deprivation consequences, the purpose of the present study was to determine plasma ET concentrations in paradoxical sleep-deprived animals. Male Wistar rats, 3 to 4 months old (N = 10 per group), were deprived of sleep for 24 and 96 h by the platform technique and plasma ET-(1/2) was measured by radioimmunoassay. Analysis of plasma revealed that 96 h of sleep deprivation induced a significant increase in ET-(1/2) release (6.58 fmol/ml) compared to control (5.07 fmol/ml). These data show that sleep deprivation altered plasma ET-(1/2) concentrations, suggesting that such an increase may participate in the genesis of arterial hypertension and cardiorespiratory changes observed after sleep deprivation.
Behçet's disease (BD) is a systemic inflammatory vasculitis of young adults with unknown aetiology, characterised by endothelial dysfunction and occlusion in both deep venous and retinal circulation. Ocular involvement occurs in 70% of cases and is characterised by periphlebitis, periarteritis, vascular occlusion, and thrombosis leading to blindness despite vigorous treatment. Endothelin-1 (ET-1) is a vasoconstricting peptide while nitric oxide (NO) is a relaxing molecule and both are released by endothelium for blood flow regulation. Homocysteinaemia is a newly defined term connected to the increased risk of atherothrombotic and atherosclerotic systemic and retinal vascular occlusive diseases, and its role in the course of BD has not been previously described. The authors aimed to detect serum total homocysteine (tHcy), ET-1, and NO in BD and to assess if tHcy, ET-1, and NO are associated with ocular BD or disease activity.
43 consecutive patients with ocular (n = 27) or non-ocular (n = 16) BD (36.95 (SD 9.80) years, 22 male, 21 female) satisfying international criteria, and 25 age and sex matched healthy control subjects (37.88 (8.73) years, 13 male, 12 female) without a history of systemic or retinal venous thrombosis were included in this study. Patients were examined by two ophthalmologists with an interest in BD. Serum tHcy, ET-1, and NO concentrations were measured in both groups. Hyperhomocysteinaemia was defined as a tHcy level above the 95th percentile in the control group. Patients were divided into active and inactive period by acute phase reactants including alpha(1) antitrypsin, alpha(2) macroglobulin, erythrocyte sedimentation rate, and neutrophil count.
The overall mean serum tHcy, ET-1, and NO levels were significantly higher in patients with BD than in control subjects (tHcy = 15.83 (4.44) v 7.96 (2.66) ng/ml, p <0.001; ET-1 = 17.47 (4.33) v 5.74 (2.34) micromol/ml, p <0.001; NO = 37.60 (10.31) v 27.08 (7.76) micromol/l, p <0.001). Serum tHcy, ET-1, and NO levels were significantly higher in active patients than in inactive patients and control subjects. In addition, among patients with ocular BD, the mean tHcy levels were significantly increased and correlated with ET-1 and NO levels when compared with non-ocular disease and control subjects. All acute phase reactant levels were significantly higher in active period than in inactive stage and controls.
Elevated tHcy may be responsible for the endothelial damage in BD and may be an additional risk factor for the development of retinal vascular occlusive disease, contributing to the poor visual outcome in these patients. Assessment of tHcy may be important in the investigation and management of patients with BD, especially with ocular disease.
Homocysteine metabolism is altered in diabetic patients. Cystathionine beta-synthase (CBS), a key enzyme involved in the transsulfuration pathway, which irreversibly converts homocysteine to cysteine, catalyzes the condensation of serine and homocysteine to cystathionine. Studies in streptozotocin-induced diabetic rats have shown that CBS enzyme activity is elevated in the liver but not in the kidney, and this effect is reversed by insulin treatment. To determine whether these effects resulted from alterations at the level of gene transcription, CBS mRNA was measured in diabetic and insulin-treated diabetic rats. CBS mRNA levels were found to be markedly higher in streptozotocin-induced diabetic rat livers; these were reduced by insulin administration. In H4IIE cells, a rat hepatoma cell culture model, glucocorticoids increased the cellular levels of CBS enzyme protein and CBS mRNA; insulin inhibited this stimulatory effect. Treatment with insulin also decreased CBS levels in HepG2 cells, a human hepatoma cell line. Nuclear run-on experiments in the rat cells confirmed that stimulation of CBS gene expression by glucocorticoids and the inhibition by insulin occurred at the transcriptional level. Transient transfections of HepG2 cells with a CBS-1b promoter luciferase reporter construct showed that the promoter activity was decreased by 70% after insulin treatment. These results show that insulin has a direct role in regulating homocysteine metabolism. Altered insulin levels in diseases such as diabetes may influence homocysteine metabolism by regulating the hepatic transsulfuration pathway.
The cardiovascular impact of stress depends on, first individual perception of stress and second individual cardiovascular reactivity to a stressful stimulation. Psychological stressors are filtered by cognitive appraisal mechanisms before causing biological response so that, for the same strain, individual effects may differ. Therefore, due to complexity of stress personal management, a multilevel stress measurement strategy is needed. To measure stress cardiovascular impact, stress should be precisely quantified. Recently, questionnaires have been developed to score not only the strain but also the personal perception of the strain. Individual stress reactivity can be evaluated by hormone response (epinephrine, norepinephrine, steroids) or by cardiovascular reactivity to a stress test. Until now, all the studies found that stress was independently related to blood pressure especially in active people. Prospective studies are still ongoing to definitively prove that stress could explain hypertension in a subset of hypertensives.
L’hyperhomocystéinémie est considérée comme un facteur de risque indépendant des pathologies cardiovasculaires occlusives. Les sujets atteints d’homocystinurie ont des homocystéinémies très élevées et présentent dès leur enfance des accidents vasculaires, thromboemboliques ou liés à l’athérosclérose. Plusieurs études cliniques et épidémiologiques de type prospectif ou rétrospectif réalisées parmi des populations à risque cardiovasculaire montrent qu’une hyperhomocystéinémie modérée est associée à un risque accru de coronaropathie, de pathologies cérébrovasculaire et vasculaire périphérique. Cependant, une telle relation n’a pas été retrouvée de façon constante chez les populations indemnes de facteurs de risque de pathologies cardiovasculaires et la mutation de la méthylènetétrahydrofolate réductase qui résulte en une augmentation de l’homocystéinémie n’est pas associée à une augmentation du risque cardiovasculaire. Il apparaît alors que seuls les essais d’intervention en cours et qui visent à étudier les effets de la diminution de l’homocystéinémie par la supplémentation par les vitamines du groupe B sur les pathologies cardiovasculaires, pourront déterminer si l’hyperhomocystéinémie modérée est un simple indicateur ou un facteur de risque cardiovasculaire.
We have shown that a psychological stressor can elicit increases in plasma AVP levels in normal human subjects. Since AVP can enhance the release of ACTH, and the pituitary gland is outside the blood-brain barrier, AVP present in the general circulation might extend the time course of stress-induced, CRF-mediated release of ACTH from the anterior lobe. Since PRA is involved in the synthesis of angiotensin I, the precursor of AII, and AII is known to enhance CRF-mediated release of ACTH from pituitary cells and to stimulate release of AVP, it is possible that the increase in PRA also contributed to the release of AVP and ACTH in this study. Reports differ as to whether circulating catecholamines can release ACTH in vivo by direct action on the pituitary. Finally, it has been reported that beta-EP enhances the release of PRL, and inhibits release of AVP. Since the increase in beta-EP in the present study was quite robust, it might have extended the PRL release, and truncated the AVP response.
The effect of graded levels of stressor intensity on anterior pituitary hormones was studied in adult male rats. Corticosterone, considered as a reflection of ACTH release, and prolactin responses showed a good correlation with the intensity of the stressors. On the contrary, neither LH, GH nor TSH release showed a parallelism with the intensity of the stressors in spite of the fact that they clearly responded to all the stimuli. It appears that the hormones of the anterior pituitary might be divided into two groups: those whose response is sensitive to the levels of emotional arousal elicited by stress, and those displaying a clear but stereotyped response during stress. However, other alternative explanations might exist to justify the present results. The neural mechanisms underlying the two types of response are at present unknown. These data indicate that only the pituitary-adrenal axis and prolactin have some potential utilities as quantitative indices of emotional arousal elicited by currently applied stressors in the rat.
The neuroendocrine and neurochemical responses of rats to 5 min of cold exposure versus 5 min of forced immobilization were determined and compared. We found that plasma hormones and brain neurochemical systems responded differently to the two different stressors. Plasma prolactin levels were elevated over 10-fold in the immolilized group, while rising only 2-fold in the cold stress group. Levels of corticosterone were significantly increased and growth hormone levels were decreased in both stressed groups as compared to controls. Levels of cyclic GMP were markedly elevated in 11 brain regions following cold exposure. Surprisingly, no elevation of cyclic GMP was found after forced immobilization. Cyclic AMP, norepinephrine, and dopamine levels throughout the 17 regions of brain examined showed no significant response to 5 min of either stressor. Lesions of the ventral medial tegmental area did not affect the cyclic GMP or neuroendocrine responses to cold stress. Lesion of the nucleus locus ceruleus did not affect the cyclic GMP response but significantly reduced growth hormone levels in the cold-stressed rats.
Although it is frequently hypothesized that perturbations of the body's principal axes of neuroendocrine response, especially the sympathetic-adrenomedullary and pituitary-adrenocortical systems, mediate psychosocial influences on disease, evidence directly supporting this hypothesis is sparse at best and, for most disease entities, nonexistent. In this article, we illustrate a research strategy aimed at elucidating the role of behavior in disease pathogenesis by focusing on a single pathologic process--disease of the coronary vasculature--and emphasizing experimental evidence linking such disease to both behavior and sympathoadrenal activation in nonhuman primates. In cynomolgus monkeys, it is found that several psychosocial variables, e.g., social instability, behavioral dominance (in males), and subordination (in females), promote coronary atherogenesis, either independently or in interaction. Animals exhibiting a heightened cardiac responsivity to stress (reactions of probable sympathetic origin) also develop the most extensive coronary lesions and beta-adrenoreceptor blockade prevents the behavioral exacerbation of atherosclerosis. Social stress causes injury to arterial endothelium (also preventable by adrenoreceptor blockade) and, among chronically stressed animals, impairs endothelium-dependent vasomotor responses of the coronary arteries. It is suggested that similar research programs might elucidate the influence of behavior and neuroendocrine factors on the pathogenesis of other disease states and conditions, including susceptibility to infection.
Oxidative stress is a cellular or physiological condition of elevated concentrations of reactive oxygen species that cause molecular damage to vital structures and functions. Several factors influence the susceptibility to oxidative stress by affecting the antioxidant status or free oxygen radical generation. Here, we review the effect of alcohol, air pollution, cigarette smoke, diet, exercise, non-ionizing radiation (UV and microwaves) and psychological stress on the development of oxidative stress. Regular exercise and carbohydrate-rich diets seem to increase the resistance against oxidative stress. Air pollution, alcohol, cigarette smoke, non-ionizing radiation and psychological stress seem to increase oxidative stress. Alcohol in lower doses may act as an antioxidant on low density lipoproteins and thereby have an anti-atherosclerotic property.
Selye defined stress as the nonspecific response of the body to any demand. Stressors elicit both pituitary-adrenocortical and sympathoadrenomedullary responses. One can test Selye's concept by comparing magnitudes of responses at different stress intensities and assuming that the magnitudes vary with stress intensity, with the prediction that, at different stress intensities, ratios of increments neuroendocrine responses should be the same. We measured arterial plasma ACTH, norepinephrine, and epinephrine in conscious rats after hemorrhage, intravenous insulin, subctaneous formaldehyde solution, cold, or immobilization. Relative to ACTH increments, cold evoked large norepinephrine responses, insulin large epinephrine responses, and hemorrhage small norepinephrine and epinephrine responses, whereas immobilization elicited large increases in levels of all three compounds. The ACTH response to 25% hemorrhage exceeded five times that to 10%, and the epinephrine response to 25% hemorrhage was two times that to 10%. The ACTH response to 4% formaldehyde solution was two times that to 1%, and the epinephrine response to 4% formaldehyde solution exceeded four times that to 1%. These results are inconsistent with Selye's doctrine of nonspecificity and the existence of a unitary "stress syndrome," and they are more consistent with the concept that each stressor has its own central neurochemical and peripheral neuroendocrine "signature."
Homocysteine is an amino acid that has been strongly associated with vascular disease. Plasma homocysteine concentrations are known to vary with dietary patterns and to decrease with exogenous estrogen use, but no other behavioral factors have been examined as potential modifiers of this risk factor. Because psychological stress has also been implicated in the development of cardiovascular disease, the purpose of this study was to test the hypothesis that acute psychological stress induces elevations in plasma homocysteine concentrations. A secondary aim was to test potential differences in response between premenopausal and postmenopausal women. Thirty-four healthy women, one-half of whom were naturally postmenopausal with no hormone replacement, participated in this study. The psychological stressors included standard mental arithmetic and speech stressors. Blood samples were taken prior to, during, and after the stressors, and heart rate and blood pressure were also monitored. Results indicated significant elevations in plasma homocysteine during acute psychological stress, with a return to baseline concentrations during recovery. The pattern of findings for blood pressure and heart rate was similar, suggesting that the rise in homocysteine concentrations may have been sympathetically-mediated. No effects of menopausal status or endogenous estrogens were found. The findings provide preliminary evidence that plasma homocysteine may be an important factor in the relationship between psychological stress and risk for heart disease.
We have used a combination of in vivo and in vitro techniques to measure factors regulating homocysteine metabolism and the plasma concentration of this atherogenic amino acid. The germane findings include: 1. Homocysteine metabolism in rat kidney proceeds predominantly through the transsulfuration pathway, whose enzymes are enriched within the proximal cells of kidney tubules. Furthermore, the rat kidney possesses significant reserve capacity to handle both acute and chronic elevations in plasma homocysteine concentrations. 2. Plasma homocysteine concentrations are lower in diabetic rats. Insulin administration corrects this perturbation. Therefore, insulin and/or one of its counter-regulatory hormones affects homocysteine metabolism, possibly through an increased flux in the hepatic transsulfuration pathway. In support of these data, glucagon administration to rats produced similar results. Further support was provided by studies with isolated rat hepatocytes, from which homocysteine export was reduced when incubated in the presence of glucagon.
Nygård O, Vollset SE, Refsum H, Brattström L, Ueland PM (University of Bergen, Norway; County Hospital, Kalmar, Sweden). Total homocysteine and cardiovascular disease (Review). J Intern Med 1999; 246: 425–454.
Recent data have shown that an elevated plasma level of the amino acid homocysteine (Hcy) is a common, independent, easily modifiable and possibly causal risk factor for cardiovascular disease (CVD) which may be of equal importance to hypercholesterolemia, hypertension and smoking. This paper reviews the biochemical, clinical, epidemiological and experimental data underlying this conclusion and is critically questioning whether elevated tHcy is a causal factor.
There is mounting evidence that inflammation plays a role in the development of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemiological data also implicate infection in remote sites in the aetiology of CHD. In this article we propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in several mechanisms that contribute to the development of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is associated with elevated levels of fibrinogen, a strong risk factor for CHD, with autocrine and paracrine activation of monocytes by IL-6 in the vessel wall contributing to the deposition of fibrinogen. The acute phase response is associated with increased blood viscosity, platelet number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol levels. IL-6 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the progression of atherosclerosis. Both these cytokines induce the release of IL-6 from several cell types, including SMC. During vascular injury SMC are exposed to platelets or their products, and cytokine production by SMC further contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance. Thus we propose a role for IL-6 in the pathogenesis of CHD through a combination of autocrine, paracrine and endocrine mechanisms. This hypothesis lends itself to testing using interventions to influence IL-6 secretion and actions.
Homocysteine does not occur in the diet but it is an essential intermediate in normal mammalian metabolism of methionine. Each compound, methionine or homocysteine, is the precursor of the other. Similarly, the synthesis of one is the mechanism for the detoxification of the other. The ubiquitous methionine cycle is the metabolic basis for this relationship. In some tissues the transsulfuration pathway diverts homocysteine from the cycle and provides a means for the synthesis of cysteine and its derivatives. Methionine, (or homocysteine) metabolism is regulated by the disposition of homocysteine between these competing sequences. Both pathways require vitamin-derived cofactors, pyridoxine for transsulfuration and both folate and cobalamin in the methionine cycle. The clinical consequences of disruption of these pathways was apparent first in rare inborn errors of metabolism that cause homocystinuria, but recent studies focus on "hyperhomocysteinemia"--a lesser metabolic impairment that may result from genetic variations, acquired pathology, toxicity and nutritional inadequacy. Hyperhomocysteinemia is an independent risk factor for thrombovascular diseases however it is not clear whether the minimally increased concentration of the amino acid is the causative agent or merely a marker for the pathology. Until we resolve that question we cannot predict the potential efficacy of therapies based on folate administration with or without additional cobalamin and pyridoxine.
Homocysteine is a sulphur amino acid that is positively associated with risk of vascular disease. Very few behavioral or psychological factors have been studied in relationship to homocysteine levels, despite the fact that several psychological factors have also been linked with risk for cardiovascular disease. One psychological attribute showing a strong association with risk is hostility, which is prospectively predictive of future cardiovascular disease endpoints. Another related psychological factor is anger expression; coronary heart disease risk is associated with both heightened expression and inhibition of anger. The purpose of this study was to test the relationship of hostility and anger expression with homocysteine concentrations in a sample of healthy, middle-aged men and women. Participants completed the Cook-Medley hostility questionnaire, the Speilberger Anger Expression questionnaire, and had blood taken for the assessment of plasma homocysteine concentrations. Results indicated positive and significant associations between hostility and homocysteine levels for all participants, and positive and significant correlations between anger-in and homocysteine levels for men only. These data are among the first to test the relationship between homocysteine and psychological risk factors for cardiovascular diseases, and suggest one potential mechanism for the increased cardiovascular risk associated with hostility and anger expression.
The purpose of this study was to determine the effects of exercise and weight loss on cardiovascular responses during mental stress in mildly to moderately overweight patients with elevated blood pressure. Ninety-nine men and women with high normal or unmedicated stage 1 to stage 2 hypertension (systolic blood pressure 130 to 179 mm Hg, diastolic blood pressure 85 to 109 mm Hg) underwent a battery of mental stress tests, including simulated public speaking, anger recall interview, mirror trace, and cold pressor, before and after a 6-month treatment program. Subjects were randomly assigned to 1 of 3 treatments: (1) aerobic exercise, (2) weight management combining aerobic exercise with a behavioral weight loss program, or (3) waiting list control group. After 6 months, compared with control subjects, participants in both active treatment groups had lower levels of systolic blood pressure, diastolic blood pressure, total peripheral resistance, and heart rate at rest and during mental stress. Compared with subjects in the control group, subjects in the exercise and weight management groups also had greater resting stroke volume and cardiac output. Diastolic blood pressure was lower for the weight management group than for the exercise-only group during all mental stress tasks. These results demonstrate that exercise, particularly when combined with a weight loss program, can lower both resting and stress-induced blood pressure levels and produce a favorable hemodynamic pattern resembling that targeted for antihypertensive therapy.
Recent evidence suggests that an increased plasma concentration of the sulphur amino acid homocysteine is a risk factor for the development of vascular disease. The tissue(s) responsible for homocysteine production and export to the plasma are not well known. However, given the central role of the liver in amino acid metabolism, we developed a rat primary hepatocyte model in which homocysteine (and cysteine) production and export were examined. The dependence of homocysteine export from incubated hepatocytes on methionine concentration fitted well to a rectangular hyperbola, with half-maximal homocysteine export achieved at methionine concentrations of approx. 0.44 mM. Hepatocytes incubated with 1 mM methionine and 1 mM serine (a substrate for the transulphuration pathway of homocysteine removal) produced and exported significantly less homocysteine (25-40%) compared with cells incubated with 1 mM methionine alone. The effects of dietary protein on homocysteine metabolism were also examined. Rats fed a 60% protein diet had a significantly increased total plasma homocysteine level compared with rats fed a 20% protein diet. In vitro effects of dietary protein were examined using hepatocytes isolated from animals maintained on these diets. When incubated with 1 mM methionine, hepatocytes from rats fed the high protein diet exported significantly more homocysteine compared with hepatocytes from rats fed the normal protein diet. Inclusion of serine significantly lowered homocysteine export in the normal protein group, but the effect was more marked in the high protein group. In vivo effects of serine were also examined. Rats fed a high protein diet enriched with serine had significantly lower total plasma homocysteine (25-30%) compared with controls. These data indicate a significant role for the liver in the regulation of plasma homocysteine levels.
Interestingly, plasma total homocysteine (tHcy) concentration is consistently higher in men than in women. This observation deserves further investigations because elevated tHcy concentrations have been shown to be independently associated with coronary, peripheral, and cerebral vascular diseases. It was the aim of the present study to define major determinants of plasma tHcy in a healthy middle-aged German population under particular consideration of the gender factor. The study population was obtained from an ongoing recruitment procedure for a cohort study and comprised 336 men and women, aged 40 to 65 years. Exclusion criteria were elevated creatinine levels in blood, history of skin or atherosclerotic diseases, current use of vitamins or other supplements, and heavy smoking. Plasma tHcy, folate, vitamin B12, vitamin B6, creatinine, testosterone and estradiol, protein, and hematocrit were measured. Fat-free mass was assessed by skinfold thickness. The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR), a key enzyme of folate and homocysteine metabolism, was determined by polymerase chain reaction (PCR) with restriction enzyme analysis. In this population, plasma tHcy ranged from 5 to 46 micromol/L. The frequency of the T allele of the MTHFR was 0.29, which is lower than in other populations. A total of 54.2% of this population was homozygote for the wild-type, 39.6% heterozygote, and 6.2% homozygote for the mutation. tHcy correlated negatively with folate and cobalamin concentration in blood and positively with creatinine. No correlation was seen with vitamin B6. From the gender-related variables, tHyc correlated significantly with fat-free mass and testosterone and inversely with estradiol. The difference between gender with regard to tHcy was mainly explained by differences in fat-free mass, but also by estradiol concentrations. The following contributions to the variation of tHcy were seen in a multivariate regression model: plasma cobalamin (11%), creatinine (11%), plasma folate (8%), fat-free mass (5%), estradiol (2%), MTHFR polymorphisms (2%), and plasma protein (1%). We concluded that tHcy in the general population has a variety of determinants ranging from nutrition, internal metabolic parameters to gender-related variables.
Hyperhomocysteinemia is a well established risk factor for cardiovascular disease, and multiple factors likely lead to abnormal regulation of plasma homocysteine in patients with diabetes. To examine a possible role for insulin and glucose in homocysteine metabolism, we examined the activity of two important enzymes of homocysteine metabolism in hepatocytes. In various tissues of six mice, methylene tetrahydrofolate reductase (MTHFR) activity was present in all tissues tested and the highest concentration (per gram) was in the brain. In contrast, cystathionine beta-synthase (CBS) activity appeared to be present only in the liver and to a small extent in the kidney. Using HEP G2 cells in culture, MTHFR activity was 3.3+/-0.8 nmol/h when the glucose concentration in the medium was 100 mg/dl and fell to 2.3+/-0.3 nmol/h when glucose was increased to 300 mg/dl. MTHFR activity was 3.4+/-0.3 nmol/h when cells were exposed to an insulin concentration of 5 mU/ml and fell to 2.8+/-0.3 nmol/h when insulin concentration was increased to 200 mU/ml (P<0.01). In contrast CBS activity increased from 0.017 to 0.13 U/ml by increasing the glucose concentration in the medium (P<0.01), but decreased from 0.04 to 0.02 (P<0.01) when the insulin concentration was increased from 5 to 200 mU/ml, respectively. We conclude that CBS and MTHFR have different tissue distributions, with CBS being present predominantly in liver and kidney, and MTHFR found in many tissues. In addition, both insulin and glucose affect the activity of the two enzymes when added to hepatocytes in vitro. If such effects occur in humans with hyperglycemia and hyperinsulinemia, then alterations in homocysteine metabolism may contribute to the accelerated macrovascular disease associated with insulin resistance or type 2 diabetes.
Various psychosocial factors have been implicated in the etiology and pathogenesis of certain cardiovascular diseases such as atherosclerosis, now considered to be the result of a chronic inflammatory process. In this article, we review the evidence that repeated episodes of acute psychological stress, or chronic psychologic stress, may induce a chronic inflammatory process culminating in atherosclerosis. These inflammatory events, caused by stress, may account for the approximately 40% of atherosclerotic patients with no other known risk factors. Stress, by activating the sympathetic nervous system, the hypothalamic-pituitary axis, and the renin-angiotensin system, causes the release of various stress hormones such as catecholamines, corticosteroids, glucagon, growth hormone, and renin, and elevated levels of homocysteine, which induce a heightened state of cardiovascular activity, injured endothelium, and induction of adhesion molecules on endothelial cells to which recruited inflammatory cells adhere and translocate to the arterial wall. An acute phase response (APR), similar to that associated with inflammation, is also engendered, which is characterized by macrophage activation, the production of cytokines, other inflammatory mediators, acute phase proteins (APPs), and mast cell activation, all of which promote the inflammatory process. Stress also induces an atherosclerotic lipid profile with oxidation of lipids and, if chronic, a hypercoagulable state that may result in arterial thromboses. Shedding of adhesion molecules and the appearance of cytokines, and APPs in the blood are early indicators of a stress-induced APR, may appear in the blood of asymptomatic people, and be predictors of future cardiovascular disease. The inflammatory response is contained within the stress response, which evolved later and is adaptive in that an animal may be better able to react to an organism introduced during combat. The argument is made that humans reacting to stressors, which are not life-threatening but are "perceived" as such, mount similar stress/inflammatory responses in the arteries, and which, if repetitive or chronic, may culminate in atherosclerosis.
Hyperhomocysteinemia has been associated with pathological and stressful conditions and is a risk factor for cardiovascular disease. Since sleep deprivation is a stressful condition that is associated with disruption of various physiological processes, we investigated whether it would also be associated with increases in plasma homocysteine levels. Further, since hyperhomocysteinemia may promote oxidative stress, and we had previously found evidence of oxidative stress in brain following sleep deprivation, we also searched for evidence of systemic oxidative stress by measuring glutathione and thiobarbituric acid reactive substance levels. Rats were sleep deprived for 96 h using the platform technique. A group was killed after sleep deprivation and another two groups were allowed to undergo sleep recovery for 24 or 48 h. Contrary to expectation, plasma homocysteine was reduced in sleep-deprived rats as compared with the control group and did not revert to normal levels after 24 or 48 h of sleep recovery. A trend was observed towards decreased glutathione and increased thiobarbituric acid reactive substance levels in sleep-deprived rats. It is possible that the observed decreases in homocysteine levels may represent a self-correcting response to depleted glutathione in sleep-deprived animals, which would contribute to the attenuation of the deleterious effects of sleep deprivation.
To investigate the effects of estrogen (E) and psychological stress on plasma total homocysteine levels in relation to menopausal status.
Double-blind, randomized, placebo-controlled study.
The General Clinical Research Center of a university hospital.
Thirty-six postmenopausal women and 26 premenopausal women. Both samples were healthy nonsmokers.
Both premenopausal and postmenopausal women were subjected to a 6-minute psychological stressor. Postmenopausal women were randomized to one of three treatment arms: 2 mg of E2 or 2 mg of E2 + 5 mg of medroxyprogesterone acetate (MPA), or a placebo, all of which were given orally for 3 months. The psychological stressor was readministered after the 3-month regimen.
Plasma total homocysteine levels were measured before and after the psychological stressor on one occasion for premenopausal women and before and after hormone replacement or placebo for postmenopausal women.
There were no significant differences in homocysteine levels between premenopausal (7.2 +/- 1.7 micromol/L; mean +/- SD) and postmenopausal women (7.9 +/- 2.06; mean +/- SD). There was no effect of stress or hormone replacement on homocysteine levels.
Psychological stress, menopausal status, and oral hormone replacement therapy (HRT) do not affect plasma total homocysteine levels in women with normal basal homocysteine levels.
In certain tissues, glutathione biosynthesis is connected to methionine metabolism via the trans-sulfuration pathway. The latter condenses homocysteine and serine to cystathionine in a reaction catalyzed by cystathionine beta-synthase followed by cleavage of cystathionine to cysteine and alpha-ketoglutarate by gamma-cystathionase. Cysteine is the limiting amino acid in glutathione biosynthesis, and studies in our laboratory have shown that approximately 50% of the cysteine in glutathione is derived from homocysteine in human liver cells. In this study, we have examined the effect of pro- and antioxidants on the flux of homocysteine through the trans-sulfuration pathway in the human hepatoma cell line, HepG2. Our studies reveal that pyrrolidine dithiocarbamate and butylated hydroxyanisole enhance the flux of homocysteine through the trans-sulfuration pathway as has been observed previously with the pro-oxidants, H(2)O(2) and tertiary butyl hydroperoxide. In contrast, antioxidants such as catalase, superoxide dismutase and a water-soluble derivative of vitamin E elicit the opposite effect and result in diminished flux of homocysteine through the trans-sulfuration pathway. These studies provide the first evidence for the reciprocal sensitivity of the trans-sulfuration pathway to pro- and antioxidants, and demonstrate that the upstream half of the glutathione biosynthetic pathway (i.e. leading to cysteine biosynthesis) is redox sensitive as is the regulation of the well-studied enzymes in the downstream half (leading from cysteine to glutathione), namely, gamma-glutamyl-cysteine ligase and glutathione synthetase.
A raised plasma level of the amino acid homocysteine is associated with increased risk of cardiovascular disease. This association may be causal—it is biologically plausible, fairly strong, graded, and an increase in plasma homocysteine preceeds the onset of vascular disease.
Plasma homocysteine levels are controlled by genetic and nutritional factors, notably folate, vitamin B12 and vitamin B6 intakes. Folic acid in particular lowers plasma homocysteine levels by about 25%. It is not known if this cheap and safe treatment reduces vascular disease risk. Current randomized control trials are addressing this issue, and proof or otherwise of causality must await their results.
Homocysteine may also interact with conventional risk factors such as smoking to substantially increase their effect on risk. Thus meticulous risk factor control may be particulary important in subjects at high total cardiovascular risk who also have a raised plasma homocysteine level, and folic acid supplementation may be considered in such individuals.
The relationship among cardiovascular disease (CVD) morbidity, risk factors (including stress), and the perception of health among male law enforcement officers (LEOs) compared to men in the general population were examined in this study. Self reported prevalence of CVD and CVD risk factors among currently employed male LEOs from nine states (n = 2,818) were compared to those of other men in the same states (n = 9,650 for CVD risk factors, n = 3,147 for CVD prevalence). Perceived stress in LEOs was assessed to determine if it affected the relationship between CVD prevalence and CVD risk factors. Cross tabulated simple percentages showed CVD was less prevalent in the LEO group than among the general population. The best predictor variables for CVD were perceived stress, time in the profession, and hypertension. The LEO group had greater prevalence of hypercholesterolemia, overweight, and tobacco use than the general population. However, a greater percentage of LEOs perceived their health as "good to excellent" compared to men in the general population. Using multivariate analysis of variance (MANOVA) it was determined that perceived stress was associated with CVD in the LEO group and three CVD risk factors (i.e., cholesterol, hypertension, physical activity) were significantly affected by perceived stress. Among susceptible officers, stress may contribute to CVD development as well as potentiate several CVD risk factors. However, an apparent lack of association exists between perception of general health and CVD risk in LEOs.
Atherosclerotic vascular disease is an enormous public health problem. A number of emerging risk factors for atherosclerosis have recently been proposed to help identify high-risk individuals.
To review the epidemiological, basic science, and clinical trial evidence concerning 4 emerging risk factors: C-reactive protein, lipoprotein(a), fibrinogen, and homocysteine.
Using the terms atherosclerosis, cardiovascular disease, risk factors, prevention, screening, C-reactive protein, lipoprotein(a), fibrinogen, and homocysteine, we searched the MEDLINE database from January 1990 to January 2003. Conference proceedings, abstract booklets, bibliographies of pertinent articles and books, and personal files were hand searched to identify additional articles.
Original investigations and reviews of the epidemiology of atherosclerosis and the association of conventional and novel risk factors with vascular risk were selected. On the basis of the search strategy, 373 relevant studies were identified.
A diverse array of studies were examined, including randomized controlled trials, prospective cohort studies, systematic overviews, case-control, cross-sectional, and mechanistic studies. Data extraction was performed by one of the authors.
The available epidemiological and basic science evidence supports, to varying degrees, independent associations between these 4 candidate risk factors and atherosclerotic vascular disease. However, there is relatively little data regarding the additive yield of screening for these factors over that of validated global risk assessment strategies currently in use. Furthermore, controlled intervention studies targeting individuals with these factors for proven risk-reduction therapies, or specifically treating these factors with available therapies, are few. The explanatory power of the major, established cardiovascular risk factors has been systematically underestimated.
Although C-reactive protein, lipoprotein(a), fibrinogen, and homocysteine are associated with vascular disease risk, their optimal use in routine screening and risk stratification remains to be determined.
L’hyper-homocyste ´ine ´mie: facteur de risque cardiovasculaire ou simple mar-queur? 2. Donne ´es e ´pide ´miologiques
- Jc Guilland
- A Favier
- Potier
- G Courcy
- P Galan
- Hercberg
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Sleep deprivation increases endothelin-1 levels. Braz
- Gabriel A Jr
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- Jc Guilland
- A Favier
- G Potier De Courcy
- P Galan
- S Hercberg
- L 'hyperhomocystéinémie
Guilland JC, Favier A, Potier de Courcy G, Galan P, Hercberg S. L'hyperhomocystéinémie: facteur de risque cardiovasculaire ou simple marqueur? 2. Données e ´pidémiologiques. Pathol Biol (Paris) 2003;51:
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- Jd Finkelstein
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- Homocysteine
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