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We investigated the role of primary haemostasis, fibrinolysis, nitric oxide (NO) and oxidative stress as well as mineralocorticoid receptors (MR) in acute aldosterone prothrombotic action.
Venous thrombosis was induced by stasis in Wistar rats. Aldosterone (ALDO; 10, 30, 100 µg/kg/h) was infused for 1 h. Eplerenone (EPL; 100 mg/kg, p.o.), a selecti...
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... On the other hand, we highlight that a clinical 2022 study found that galectin-3 accumulation potentiates platelet aggregation via dectin-1 activation [109], which can promote thrombosis during/or following exercise. [117,118], triggering a cascade of coagulation. We believe that aldosterone can play a crucial role in the development of thrombosis, resulting in cardiovascular dysfunction during and following endurance exercise. ...
Exercise mechanical efficiency typically falls within the range of approximately 20 to 25%. This means that a great part of the metabolic energy converted to generate movement is released as heat. Therefore, the rise in core temperature during endurance exercise in humans is proportional to generated work. Cutaneous vasodilation occurs when the core temperature threshold is reached. The rise in heart rate in response to thermal stress is a cardiovascular response that increases cardiac output and skin blood flow. The cardiovascular response during endurance exercise is a complex phenomenon potentially influenced by the involvement of nitric oxide in active thermoregulatory vasodilation. Excessive exercise can create high oxidative stress by disrupting the balance between free radicals’ production and scavenging, resulting in impaired cardiovascular function. The above considerations are related to the severity and duration of endurance exercise. The first focus of this narrative review is to provide an updated understanding of cardiovascular function during endurance exercise. We aim to explore the potential role of oxidative stress in causing cardiovascular dysfunction during endurance exercise from a fresh perspective. Additionally, we aim to identify the primary factors contributing to cardiovascular risk during strenuous prolonged exercise by highlighting recent progress in this area, which may shed light on previously unexplained physiological responses. To ascertain the effect of endurance exercise on cardiovascular function and dysfunction, a narrative review of the literature was undertaken using PubMed, ScienceDirect, Medline, Google Scholar, and Scopus. The review highlighted that high oxidative stress (due to high levels of catecholamines, shear stress, immune system activation, and renal dysfunction) leads to a rise in platelet aggregation during endurance exercise. Importantly, we clearly revealed for the first time that endothelial damage, vasoconstriction, and blood coagulation (inducing thrombosis) are potentially the primary factors of cardiovascular dysfunction and myocardial infarction during and/or following endurance exercise.
... Aldosterone levels are positively correlated with an increased risk of acute cardiovascular thrombotic events [9]. This aldosterone effect is related to enhanced coagulation, reduced fibrinolysis, increased oxidative stress, and reduced nitric oxide bioavailability [74]. MR antagonists and angiotensin II receptor antagonists do not completely suppress the prothrombotic effect of aldosterone [75]. ...
... Aldosterone administration promoted stasis-induced venous thrombosis in rats and laser-or FeCl 3 -induced thrombosis in mesenteric venules in mice [74,79]. The aldosterone mechanism of the prothrombotic action is related to its rapid and simultaneous effects on platelets, plasma-and endothelium-dependent hemostatic factors, and alterations in the clot structure, thereby making it resistant to fibrinolysis. ...
Aldosterone, a vital hormone of the human body, has various pathophysiological roles. The excess of aldosterone, also known as primary aldosteronism, is the most common secondary cause of hypertension. Primary aldosteronism is associated with an increased risk of cardiovascular disease and kidney dysfunction compared to essential hypertension. Excess aldosterone can lead to harmful metabolic and other pathophysiological alterations, as well as cause inflammatory, oxidative, and fibrotic effects in the heart, kidney, and blood vessels. These alterations can result in coronary artery disease, including ischemia and myocardial infarction, left ventricular hypertrophy, heart failure, arterial fibrillation, intracarotid intima thickening, cerebrovascular disease, and chronic kidney disease. Thus, aldosterone affects several tissues, especially in the cardiovascular system, and the metabolic and pathophysiological alterations are related to severe diseases. Therefore, understanding the effects of aldosterone on the body is important for health maintenance in hypertensive patients. In this review, we focus on currently available evidence regarding the role of aldosterone in alterations of the cardiovascular and renal systems. We also describe the risk of cardiovascular events and renal dysfunction in hyperaldosteronism.
... However, even higher dose ranges have been used in many in vitro as well as in vivo studies investigating the mechanism of ALDO action [20,35,43,51]. ALDO levels can be extremely increased in many human pathological states, such as hypertension, primary hyperaldosteronism, heart failure, and diabetes; moreover, increased levels of ALDO were observed in patients and animals undergoing intra-abdominal surgery during the procedure, as well as in the postoperative period [58][59][60]. Second, the IHC staining was performed to evaluate the expression of commonly used vascular permeability markers. ...
The aim of this study was to evaluate the effect of acute aldosterone (ALDO) administration on the vascular permeability of skin. ALDO was injected intradermally into rats, and vascular permeability was measured. Eplerenone (EPL), a selective mineralocorticoid receptor (MR) antagonist, was used. Skin biopsies were carried out for immunohistochemical (IHC) staining, and polymerase chain reactions were performed to analyze the expression of MR, 11β-hydroxysteroid dehydrogenase type 2, von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), and zonula occludens 1. Our study showed the presence of MR in the rat skin vasculature for the first time. It was found that ALDO injection resulted in a more than 30% increase in vascular permeability and enhanced the endothelial exocytosis of vWF. The effect of ALDO diminished after EPL administration. An accumulation of vWF and a reduction in VEGF IHC staining were observed following chronic EPL administration. No effect of ALDO or EPL on the mRNA expression of the studied genes or skin structure was observed. The results suggest that ALDO increases vascular permeability in the skin via an MR-dependent mechanism. This effect of ALDO on skin microcirculation may have important therapeutic implications for diseases characterized by increased levels of ALDO and coexisting skin microangiopathy.
... Aldosterone exerts prothrombotic actions in rodents. [172][173][174][175] It is associated with platelet activation, fibrin production, and the release of procoagulant and antifibrinolytic factors. Acute aldosterone administration in rats increased the first stage of thrombus formation, the density of fibrin net, platelet aggregations, and reduced fibrinolysis. ...
... 173 In addition, aldosterone increased the incidence of venous thrombosis and PAI-1, NOX, and ROS levels, but tissue plasminogen activator decreased. 42,174 In mice, acute aldosterone administration enhanced platelet accumulation at the site of endothelial injury induced by laser. 173 After 90 days of aldosterone treatment in mice, there were enhanced platelet activation and reduced fibrinolysis in which spironolactone blocked these effects. ...
... 175 Spironolactone and eplerenone treatment decreased thrombus formation in both arteries and veins in aldosterone-treated rodents. 42,174,175 Furthermore, eplerenone reduced bleeding time, PAI-1 expression, and ROS level in rats given aldosterone infusion. 174 4.6.2 ...
Aldosterone’s role in the kidney and its pathophysiologic actions in hypertension are well known. However, its role or that of its receptor [minieralocorticoid receptor (MR)] in other cardiovascular (CV) disease are less well described. To identify their potential roles in six CV conditions (heart failure, myocardial infarction, atrial fibrillation, stroke, atherosclerosis, and thrombosis), we assessed these associations in four areas: 1) mechanistic studies in rodents and humans; 2) preclinical studies of MR antagonists; 3) clinical trials of MR antagonists; and 4) genetics. The data were acquired from an online search of the National Library of Medicine using the PubMed search engine from January 2011 through June 2021. There were 3702 publications identified with 156 publications meeting our inclusion and exclusion criteria. Data strongly supported an association between heart failure and dysregulated aldosterone/MR. This association is not surprising given aldosterone/MR’s prominent role in regulating sodium/volume homeostasis. Atrial fibrillation and myocardial infarction are also associated with dysregulated aldosterone/MR, but less strongly. For the most part, the data were insufficient to determine if there was a relationship between atherosclerosis, stroke or thrombosis and aldosterone/MR dysregulation. This review clearly documented an expanding role for aldosterone/MR’s dysregulation in CV diseases beyond hypertension. How expansive it might be is limited by the currently available data. It is anticipated that with an increased focus on aldosterone/MR’s potential roles in these diseases, additional clinical and preclinical data will clarify these relationships, thereby, opening approaches to use modulators of aldosterone/MR’s action to more precisely treat these CV conditions.
... Furthermore, the expression of pro-inflammatory cytokines was enhanced by MR activation (Jia et al., 2016). On the one hand, in models of vascular injury, MR was reported to be pro-thrombotic while, on the other hand, overexpression of MR in endothelial cells increased protein C expression and thereby attenuated thrombin generation and vascular thrombosis (Bodary et al., 2006;Gromotowicz et al., 2011;Lagrange et al., 2014). Aldosterone also induced changes in the expression of epithelial sodium channels, which led to enhanced sodium transport and changes in mechanical cell properties, which contribute to vascular stiffness and fibrosis (Kusche-Vihrog et al., 2008;Drueppel et al., 2013;DuPont et al., 2014;Jia et al., 2016). ...
During aging, the cardiovascular system is especially prone to a decline in function and to life-expectancy limiting diseases. Cardiovascular aging is associated with increased arterial stiffness and vasoconstriction as well as left ventricular hypertrophy and reduced diastolic function. Pathological changes include endothelial dysfunction, atherosclerosis, fibrosis, hypertrophy, inflammation, and changes in micromilieu with increased production of reactive oxygen and nitrogen species. The renin-angiotensin-aldosterone-system is an important mediator of electrolyte and blood pressure homeostasis and a key contributor to pathological remodeling processes of the cardiovascular system. Its effects are partially conveyed by the mineralocorticoid receptor (MR), a ligand-dependent transcription factor, whose activity increases during aging and cardiovascular diseases without correlating changes of its ligand aldosterone. There is growing evidence that the MR can be enzymatically and non-enzymatically modified and that these modifications contribute to ligand-independent modulation of MR activity. Modifications reported so far include phosphorylation, acetylation, ubiquitination, sumoylation and changes induced by nitrosative and oxidative stress. This review focuses on the different posttranslational modifications of the MR, their impact on MR function and degradation and the possible implications for cardiovascular aging and diseases.
... MR activation also induced renal endothelial dysfunction characterized by inflammatory activation, impaired vasodilation and fibrosis. (Arima et al. 2004;Oberleithner et al. 2004;Lai et al. 2006;Duprez 2007;Gromotowicz et al. 2011;Bauersachs et al. 2015). In addition, MR-mediated glomerulosclerosis could reduce the ability of capillary oxygen delivery, which could finally result in ischemic renal injuries (Hollenberg 2004;Nangaku 2006;Cowgill et al. 2016;Brown et al. 2019). ...
Aldosterone plays pivotal roles in renin-angiotensin-aldosterone system in order to maintain the equilibrium of liquid volume and electrolyte metabolism. Aldosterone action is mediated by both mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Its excessive actions directly induced tissue injuries in its target organs such as myocardial and vascular fibrosis in addition to chronic kidney diseases. Excessive aldosterone actions were also reported to be involved in unbalanced electrolyte metabolism in inflammatory bowel disease and development of pulmonary diseases. Hyperaldosteronism is tentatively classified into primary and secondary types. Primary aldosteronism is more frequent and has been well known to result in secondary hypertension with subsequent cardiovascular damages. Primary aldosteronism is also further classified into distinctive subtypes and among those, aldosterone-producing adenoma is the most frequent one accounting for the great majority of unilateral primary aldosteronism cases. In bilateral hyperaldosteronism, aldosterone-producing diffuse hyperplasia and aldosterone-producing micronodules or nodules are the major subtypes. All these aldosterone-producing lesions were reported to harbor somatic mutations including KCNJ5, CACNA1D, ATP1A1 and ATP2B3, which were all related to excessive aldosterone production. Among those mutations above, somatic mutation of KCNJ5 is the most frequent in aldosterone-producing adenoma and mostly composed of clear cells harboring abundant aldosterone synthase expression. In contrast, CACNA1D-mutated aldosterone-producing micronodules or aldosterone-producing nodules were frequently detected not only in primary aldosteronism patients but also in the zona glomerulosa of normal adrenal glands, which could eventually lead to an autonomous aldosterone production resulting in normotensive or overt primary aldosteronism, but their details have remained unknown.
... A significant correlation was also observed between serum ALDO level and PAI-1 antigen [6]. Thus, ALDO has also been proposed to be a prothrombotic factor that was confirmed in animal models [7][8][9]. The acute administration of ALDO was demonstrated to enhance venous thrombosis in rats [9] and laser-or FeCl3-induced thrombosis in mesenteric venules in mice [10]. ...
... Thus, ALDO has also been proposed to be a prothrombotic factor that was confirmed in animal models [7][8][9]. The acute administration of ALDO was demonstrated to enhance venous thrombosis in rats [9] and laser-or FeCl3-induced thrombosis in mesenteric venules in mice [10]. The compound mechanism of the prothrombotic action of ALDO is related to its rapid and simultaneous effects on platelets as well as plasma-and endothelium-dependent hemostatic factors and alteration in the clot structure, thereby making it resistant to fibrinolysis [9,10]. ...
... The acute administration of ALDO was demonstrated to enhance venous thrombosis in rats [9] and laser-or FeCl3-induced thrombosis in mesenteric venules in mice [10]. The compound mechanism of the prothrombotic action of ALDO is related to its rapid and simultaneous effects on platelets as well as plasma-and endothelium-dependent hemostatic factors and alteration in the clot structure, thereby making it resistant to fibrinolysis [9,10]. Moreover, it is known that vascular function that depends on smooth muscle cells and endothelium-dependent mechanisms affects the thrombotic process. ...
We investigated the role of aldosterone (ALDO) in the development of arterial thrombosis in streptozotocin-induced diabetic rats. To evaluate the effect of endogenous ALDO, the rats underwent adrenalectomy (ADX). ADX reduced the development of arterial thrombosis. A 1 h infusion of ALDO (30 μg/kg/h) enhanced thrombosis in adrenalectomized rats, while this effect was potentiated in diabetic rats. ALDO shortened bleeding time, increased plasma levels of tissue factor (TF) and plasminogen activator inhibitor, decreased plasma level of nitric oxide (NO) metabolites, and increased oxidative stress. Moreover, 2 h incubation of human umbilical vein endothelial cells (HUVECs) with ALDO (10−7 M) disrupted hemostatic balance in endothelial cells in normoglycemia (glucose 5.5 mM), and this effect was more pronounced in hyperglycemia (glucose 30 mM). We demonstrated that the acute ALDO infusion enhances arterial thrombosis in rats and hyperglycemia potentiates this prothrombotic effect. The mechanism of ALDO action was partially mediated by mineralocorticoid (MR) and glucocorticoid (GR) receptors and related to impact of the hormone on primary hemostasis, TF-dependent coagulation cascade, fibrinolysis, NO bioavailability, and oxidative stress balance. Our in vitro study confirmed that ALDO induces prothrombotic phenotype in the endothelium, particularly under hyperglycemic conditions.
... Template BT was measured in anesthetized rats [53]. In brief, a standard incision was made longitudinally on the surface of the tail, starting 2 to 3 cm from the tail root (9 cm from the tip), taking care to avoid the large vessels. ...
... After BT measurement, blood samples (5 mL) were drawn and collected from the RV of the heart on anticoagulant (170 mM trisodium citrate, 130 mM citric acid and 101 mM glucose) in a volume ratio of 9:1. The preparation of the washed platelets and their adhesion to fibrillar collagen was performed according to Gromotowicz et al. [53]. In brief, 250 µL washed platelet samples (at final concentration of 3 × 10 5 platelets/µL) were incubated in an Elvi aggregometer at 37 • C and stirred at 900 rpm with ethylenediaminetetraacetic acid (EDTA) solution (5 mM) to avoid platelet aggregation. ...
Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension (PH) rats. PH was connected with elevation of right ventricular systolic pressure; right ventricle hypertrophy; lung edema; pulmonary artery remodeling; enhancement of the vasoconstrictor and decreasing vasodilatory responses; increases in plasma concentrations of tissue plasminogen activator, plasminogen activator inhibitor type 1 and leukocyte count; and a decrease in blood oxygen saturation. CBD improved all abovementioned changes induced by PH except right ventricle hypertrophy and lung edema. In addition, CBD increased lung levels of some endocannabinoids (anandamide, N-arachidonoyl glycine, linolenoyl ethanolamide, palmitoleoyl ethanolamide and eicosapentaenoyl ethanolamide but not 2-arachidonoylglycerol). CBD did not affect the cardiopulmonary system of control rats or other parameters of blood morphology in PH. Our data suggest that CBD ameliorates MCT-induced PH in rats by improving endothelial efficiency and function, normalization of hemostatic alterations and reduction of enhanced leukocyte count determined in PH. In conclusion, CBD may be a safe, promising therapeutic or adjuvant therapy agent for the treatment of human pulmonary artery hypertension.
... This unbalanced activation of the coagulation cascade is further potentiated by Ang IV 25 and aldosterone. 26 ACE2 is known to play a central role in balancing the levels of Ang II and Ang IV. 27 ACE2 gene transfer has been found to suppress the expression of p22phox (a component of membrane associated enzyme phagocyte NADPH-oxidase) and Migration Inhibitory Factor (MIF) and the production of Malondialdehyde(MDA) caused by Ang II and Ang IV in human endothelial cells. 27 Therefore, ACE2 receptor loss could markedly upregulate the aminopeptidase induced Angiotensin degradation with consequent amplification of ACE 2-Ang II-Ang IV axis. ...
Coronavirus 2019 disease (COVID-19) was first recognised as an acute respiratory syndrome. Soon, it was realised that acute kidney injury, myocarditis, hyperimmune activation and prothrombotic disseminated intravascular coagulation are also part of the disease complex. Currently, it is being recognised as causing microthrombi as well as thrombo-embolic complications. The SARS-CoV-2 coronavirus enters cells via the ACE2 (Angiotensin converting enzyme-2) receptor and leads to its downregulation. The loss of ACE2 is postulated to cause activation of the Renin Angiotensin Aldosterone System (RAAS) that contributes to cardiac and renal pathology. Supporting the hypothesis that ACE2 loss can explain the entire pathology, we have reviewed the available literature to determine mechanistic associations between RAAS and the various manifestations of COVID-19.
ACE2 dependent protective pathways include the Angiotensin(1-7)/Mas receptor and Alamandine/MrgD receptor pathways. These are anti-hypertensive, anti-inflammatory, and anti-thrombotic. Loss of ACE2 leads to bradykinin and Angiotensin II accumulation that causes thrombosis via release of tissue Plasminogen Activator(tPA). Angiotensin II, with altered ACE/ACE2 balance, can activate immune cells. Animal models of various viral pneumonia have previously shown that ACE2 loss is associated with severe lung injury. Angiotensin II and aldosterone are known causes of cardiomyopathy and also potentiate acute kidney injury. There is some emerging evidence that inhibitors of canonical RAAS such as ACE inhibitors, Angiotensin receptor blockers, and statins may have mortality benefit in COVID-19. Heparin inhibits both thrombosis and RAAS, and has definite mortality benefit at least in a subset of COVID-19 patients. We strongly advocate that treatment strategies for COVID-19 should include synergistic targeting of the RAAS system.
... Endothelial dysfunction, characterized by impaired vasodilation, increased platelet and leucocyte adhesion, and decreased nitric oxide bioavailability, occurs secondary to MR activation in experimental rodent studies (Gromotowicz et al., 2011;Oberleithner et al., 2004). ...
... The endothelial nitric oxide synthase (eNOS)-nitric oxide pathway is key in maintaining endothelial integrity and function (Goligorsky, Brodsky, & Noiri, 2004). MR activation can reduce eNOS activity and cause eNOS uncoupling, resulting in impaired vasodilation (Arima et al., 2004;Bauersachs et al., 2015;Duprez, 2007;Gromotowicz et al., 2011;Liu, Schmuck, Chorazcyzewski, Gros, & Feldman, 2003). Oxidative stress, including enhanced ROS production, is another mechanism by which aldosterone reduces nitric oxide bioavailability and impairs vascular reactivity (Farquharson & Struthers, 2002;Leopold et al., 2007;Sanz-Rosa et al., 2005;Virdis et al., 2002). ...
... MRAs improve transplant-associated vasculopathy and glomerular macrophage influx (Waanders et al., 2009), protect against chronic changes induced by cyclosporine including vasoconstriction, arteriolopathy and tubulointerstitial fibrosis (Feria et al., 2003;Nielsen, Jensen, Marcussen, Skøtt, & Bie, 2008), and slow kidney damage progression in established injury (Pérez-Rojas et al., 2007). Experimental Aldosterone can also contribute to renal ischaemia by promoting microthrombi in injured or dysfunctional vessels (Brown, Kim, et al., 2000;Gromotowicz et al., 2011;Rocha et al., 2000), a process mediated by oxidative stress (Stier, 2000). MRA treatment can reduce thrombosis (Rigsby et al., 2007). ...
There is a growing body of experimental and clinical evidence supporting mineralocorticoid receptor (MR) activation as a powerful mediator of renal damage in laboratory animals and humans. Multiple pathophysiological mechanisms are proposed, with the strongest evidence supporting aldosterone‐induced vasculopathy, exacerbation of oxidative stress and inflammation, and increased growth factor signalling promoting fibroblast proliferation and deranged extracellular matrix homeostasis. Further involvement of the MR is supported by extensive animal model experiments where MR antagonists (such as spironolactone and eplerenone) abrogate renal injury, including ischaemia‐induced damage. Additionally, clinical trials have shown MR antagonists to be beneficial in human chronic kidney disease (CKD) in terms of reducing proteinuria and cardiovascular events, though current studies have not evaluated primary end points which allow conclusions to made about whether MR antagonists reduce mortality or slow CKD progression. Although differences between human and feline CKD exist, feline CKD shares many characteristics with human disease including tubulointerstitial fibrosis. This review evaluates the evidence for the role of the MR in renal injury and summarizes the literature concerning aldosterone in feline CKD. MR antagonists may represent a promising therapeutic strategy in feline CKD.
