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The core biochemical network of the ceramide/sphingosine-1-phosphate rheostat. A comprehensive core network is depicted including the possible source of free fatty acids synthesized de novo in the vascular bed (the fatty acid elongation enzyme, ELOV3), as well as the oxidative-redox system (GCLC and GCLM) which regulates neutral sphingomyelinase activity, a source of ceramides. These latter are only introduced as "summary" variables as the focus has been on the de novo pathway of ceramide synthesis. Node degrees are shown in the brackets.
Source publication
Several attempts to decipher the genetics of hypertension of unknown causes have been made including large-scale genome-wide association analysis (GWA), but only a few genes have been identified. Unsolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing monogenic approach to capture genetic effects in a polyg...
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For several decades, lipid biologists have investigated how sphingolipids contribute to physiology, cell biology, and cell fate. Foremost among these discoveries is the finding that the bioactive sphingolipids ceramide, sphingosine, and sphingosine-1-phosphate (S1P) have diverse and often opposing effects on cell fate. Interestingly, these bioactiv...
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The question of whether the distinct isoforms of the family of enzymes phosphoinositide 3-kinases (PI3Ks) play redundant roles within a cell or whether they control distinct cellular processes or distinct steps within the same cellular process has gained considerable importance in the recent years due to the development of inhibitors able to select...
Purpose
To delineate the role of Sphingolipids (SPLs) in the human cornea and their cross-talks with transforming growth factor beta (TGF-β) in order to develop novel, non-invasive therapies.
Methods
Human corneal fibroblasts (HCFs) were harvested from healthy donors, stimulated with Vitamin C to promote extracellular matrix assembly, treated with...
Metabolism of sphingolipids into downstream lipid mediators followed by signaling modulates tumor microenvironment and the cancer cells to influence tumor progression. As such, sphingolipid signaling represents a novel way to modulate tumor biology. Neuroblastoma (NB), the most common extracranial solid tumor of childhood, is highly angiogenic and...
Citations
... Sphingosine 1-kinase (SPHK1) and ceramidase (ASAH1) work together to produce ceramide. This gene pair has been linked to hypertension, providing further evidence of S1P (sphingosine 1-phosphate) and RhoA signaling involvement [21,22]. ...
Citation: Shoghli, M.; Lokki, A.I.; Lääperi, M.; Sinisalo, J.; Lokki, M.-L.; Hilvo, M.; Jylhä, A.; Tuomilehto, J.; Laaksonen, R. The Novel Ceramide-and Phosphatidylcholine-Based Risk Score for the Prediction of New-Onset of Hypertension. J. Clin. Med. 2023, 12, 7524. https://doi. These authors contributed equally to this work. Abstract: Ceramides and other sphingolipids are implicated in vascular dysfunction and inflammation. They have been suggested as potential biomarkers for hypertension. However, their specific association with hypertension prevalence and onset requires further investigation. This study aimed to identify specific ceramide and phosphatidylcholine species associated with hyper-tension prevalence and onset. The 2002 FINRISK (Finnish non-communicable risk factor survey) study investigated the association between coronary event risk scores (CERT1 and CERT2) and hypertension using prevalent and new-onset hypertension groups, both consisting of 7722 participants , over a span of 10 years. Ceramide and phosphatidylcholine levels were measured using tandem liquid chromatography-mass spectrometry. Ceramide and phosphatidylcholine ratios, including ceramide (d18:1/18:0), ceramide (d18:1/24:1), phosphatidylcholine (16:0/16:0), and the ratio of ceramide (d18:1/18:0)/(d18:1/16:0), are consistently associated with both prevalence and new-onset hypertension. Ceramide (d18:1/24:0) was also linked to both hypertension measures. Adjusting for covariates, CERT1 and CERT2 showed no-longer-significant associations with hy-pertension prevalence, but only CERT2 predicted new-onset hypertension. Plasma ceramides and phosphatidylcholines are crucial biomarkers for hypertension, with imbalances potentially contributing to its development. Further research is needed to understand the underlying mechanisms by which ceramides will contribute to the development of hypertension.
... Elevated ceramide levels have been previously associated with the development and progression of hypertension and cardiovascular disease. [39][40][41][42] In particular, ceramide scores are established predictors of cardiovascular risk. 22 23 43 44 Therefore, our results are consistent with previous studies. ...
Objective
Ceramides have been associated with several ageing-related conditions but have not been studied as a general biomarker of multimorbidity (MM). Therefore, we determined whether ceramide levels are associated with the rapid development of MM.
Design
Retrospective cohort study.
Setting
Mayo Clinic Biobank.
Participants
1809 persons in the Mayo Clinic Biobank ≥65 years without MM at the time of enrolment, and with ceramide levels assayed from stored plasma.
Primary outcome measure
Persons were followed for a median of 5.7 years through their medical records to identify new diagnoses of 20 chronic conditions. The number of new conditions was divided by the person-years of follow-up to calculate the rate of accumulation of new chronic conditions.
Results
Higher levels of C18:0 and C20:0 were associated with a more rapid rate of accumulation of chronic conditions (C18:0 z score RR: 1.30, 95% CI: 1.10 to 1.53; C20:0 z score RR: 1.26, 95% CI: 1.07 to 1.49). Higher C18:0 and C20:0 levels were also associated with an increased risk of hypertension and coronary artery disease.
Conclusions
C18:0 and C20:0 were associated with an increased risk of cardiometabolic conditions. When combined with biomarkers specific to other diseases of ageing, these ceramides may be a useful component of a biomarker panel for predicting accelerated ageing.
... Low H 2 O 2 concentrations activated nSMase2 and ShK1 through a nSMase2/ceramide-dependent signaling pathway that acts upstream of SphK1, leading to cell proliferation, while high H 2 O 2 concentrations inhibited SphK1 activity and reduced the ratio of ceramide/S1P, leading to cytotoxicity in VSMC [217]. In support of this, a rheostat of ceramide-S1P has been shown to control the blood pressure in hypertensive patients [282]. Thus, sensing the severity of oxidative stress in the cell can determine a rheostat of ceramide-S1P, which plays a crucial role in the regulation of oxidant-induced kidney injury. ...
Reactive oxygen species (ROS) modulate sphingolipid metabolism, including enzymes that generate ceramide and sphingosine-1-phosphate (S1P), and a ROS-antioxidant rheostat determines the metabolism of ceramide-S1P. ROS induce ceramide production by activating ceramide-producing enzymes, leading to apoptosis, while they inhibit S1P production, which promotes survival by suppressing sphingosine kinases (SphKs). A ceramide-S1P rheostat regulates ROS-induced mitochondrial dysfunction, apoptotic/anti-apoptotic Bcl-2 family proteins and signaling pathways, leading to apoptosis, survival, cell proliferation, inflammation and fibrosis in the kidney. Ceramide inhibits the mitochondrial respiration chain and induces ceramide channel formation and the closure of voltage-dependent anion channels, leading to mitochondrial dysfunction, altered Bcl-2 family protein expression, ROS generation and disturbed calcium homeostasis. This activates ceramide-induced signaling pathways, leading to apoptosis. These events are mitigated by S1P/S1P receptors (S1PRs) that restore mitochondrial function and activate signaling pathways. SphK1 promotes survival and cell proliferation and inhibits inflammation, while SphK2 has the opposite effect. However, both SphK1 and SphK2 promote fibrosis. Thus, a ceramide-SphKs/S1P rheostat modulates oxidant-induced kidney injury by affecting mitochondrial function, ROS production, Bcl-2 family proteins, calcium homeostasis and their downstream signaling pathways. This review will summarize the current evidence for a role of interaction between ROS-antioxidants and ceramide-SphKs/S1P and of a ceramide-SphKs/S1P rheostat in the regulation of oxidative stress-mediated kidney diseases.
... 15 Results from 2 previous experimental studies suggest that the sphingolipid system is involved in blood pressure regulation. 16,17 The central intermediate of the sphingolipid biosynthetic pathway is ceramides. 18 Ceramides can mediate vascular dysfunction by inhibiting the endothelial nitric oxide synthase/serine-threonine protein kinase/heat shock protein 90 signaling complex. ...
Background
Plasma ceramides (Cer) have been used to evaluate risk of cardiovascular events in patients with coronary heart disease. We investigated the performance of ceramides and ceramide score (CERT) in hypertensive patients at high cardiovascular risk.
Methods
Seven ceramides were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry in 920 essential hypertension patients at high cardiovascular risk, who visited Beijing Anzhen Hospital from September 2016 to September 2018 (median age: 49 years, 562 males). All patients were followed up for Major Adverse Cardiovascular Events (MACE), which included incident acute coronary syndrome, heart failure, stroke, and cardiovascular death.
Results
During mean 2.3-year follow-up, 71 patients experienced MACE. Cer(d18:1/16:0), Cer(d18:1/22:0) and Cer(d18:1/24:0)were highly significant in predicting MACE [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.76 (1.34–2.30), 0.55 (0.41–0.73) and 0.66 (0.47–0.92),, respectively]. Compared with traditional variables (comprising presence of cardiovascular risk factors, hypertension-mediated organ damage, and comorbidities), a novel CERT for hypertensive patients (CERT-HBP), composed of Cer(d18:1/16:0), Cer(d18:1/24:1), and their ratios to Cer(d18:1/24:0) and Cer(d18:1/22:0) respectively, increased the C-statistic from 0.751 (95%CI, 0.697–0.806) to 0.791 (95%CI, 0.737–0.845), p=0.010. Net reclassification improvement and integrated discrimination improvement were 0.648 (95%CI, 0.421–0.885, p<0.001) and 0.046 (95%CI, 0.025–0.068, p<0.001), respectively.
Conclusions
A ceramide-based CERT-HBP was established to evaluate risk of MACE in hypertensive patients at high cardiovascular risk. This may improve identification of high-risk patients requiring increased attention and aggressive therapy.
... Among the identified metabolites predicting blood pressure, sphingolipid ceramides, triacylglycerols, phosphatidylcholines, and phosphatidylethanolamine were the major component that mediated the associations between coarse grain intake with blood pressure [34]. Moreover, data from the Framingham Offspring Cohort suggested that increasing whole grain consumption was associated with circulating sphingolipid ceramides [35]; evidence from animal models suggested sphingolipid de novo biosynthesis was actively involved in cardiovascular homeostasis, mediating vasoconstriction and blood pressure [36,37]. Obviously, further interventional studies are needed to elucidate the effectiveness of increasing coarse grain intake in blood pressure control and the underlining metabolomic pathways. ...
Whole grain intake was associated with better blood pressure control, but evidence is lacking in non-Western populations with different grain intake patterns. We aimed to determine the associations between coarse grain intake, usually considered as the best proxy of whole grain intake for Chinese diets, with blood pressure and undiagnosed hypertension using baseline data from the China Kadoorie Biobank study. After excluding participants with clinically diagnosed hypertension or use of antihypertensive dugs, 435,907 participants were included in our analysis. A self-reported questionnaire was used to measure coarse grain intake frequency. Overall, 12.8% and 29.2% of the participants reported daily consumption and never consumption, respectively. With multivariable adjustments including BMI, outdoor temperature, and physical activity, higher frequency of coarse grain intake was associated with lower systolic and diastolic blood pressure in those older than 40 years, p trend < 0.05. Compared to never consumers, the odds ratio (95% CI) of hypertension was 0.78 (0.73–0.84), 0.84 (0.77–0.91), 0.91 (0.88–0.94), and 0.97 (0.95–0.99) for daily, 4–6 days/week, 1–3 days/week, and monthly groups, P trend < 0.001. Our cross-sectional study in a nationwide sample of Chinese adults suggests that higher coarse grain intake was associated with lower blood pressure and lower hypertension risk.
... Sphingomyelin and its metabolites influence vascular tone (Li et al., 2002;Ohmori et al., 2003) and are involved in the mechanism regulating blood pressure (Fenger et al., 2011;Spijkers et al., 2011;Fenger et al., 2015). S1P (C06124) and sphinganine (C00836) are also major biological mediators in various tissues and have been associated with the control of cell growth, differentiation, as well as programmed cell death (Spiegel and Milstien, 2003). ...
Plantaginis Semen (PS) is well recognized in traditional Chinese medicine (TCM) and health products. Crude PS (CPS) and salt-processed CPS (SPS) are the two most commonly used decoction pieces of PS, and are included in the 2020 edition of Chinese Pharmacopoeia. Although they all have multiple effects, the mechanisms for treating diseases are different and remain unclear, the processing mechanism of SPS is also indeterminate, which hinders their clinical application to a certain extent. In order to solve these problems and further develop PS in the clinical application. Here, we used saline-loaded model rats for experiments, and utilized an integrated approach consisting of pharmacological methods and metabolomics, which could assess the diuretic impact of CPS and SPS ethanol extracts on saline-loaded rats and elucidate the underlying mechanism. The results showed that CPS and SPS both produced increased urine volume excretion and urine electrolyte excretion, but the levels of aldosterone (ALD) and aquaporin 2 (AQP2) were decreased. And 30 differential metabolites such as linoleic acid, lysoPC(O-18:0), sphingosine-1-phosphate, lysoPC(18:0) were found, mainly involving three metabolic pathways. In conclusion, CPS and SPS both have a diuretic effect, and that of SPS is better. This work investigated the possible diuretic mechanisms of CPS and SPS which may also be the mechanism of PS for anti-hypertension. In addition, a holistic approach provided novel and helpful insights into the underlying processing mechanisms of TCM.
... A growing number of studies have shown that S1P and its signaling pathway may participate in BP regulation and hypertension [32][33][34]. The effect of S1P on BP is the result of changes in both vascular and heart functions. ...
Background: Salt is a crucial factor for blood pressure modulation, especially in salt-sensitive individuals. Sphingosine-1-phosphate (S1P), a pleiotropic bioactive sphingolipid metabolite participating in blood pressure regulation, has recently been identified as a novel lipid diuretic factor. However, the relationships among salt intake, circulating S1P levels, and blood pressure changes in human beings are unknown. Thus, we conducted this intervention trial to explore the effect of dietary salt intake on plasma S1P levels and to examine the relationship between S1P and blood pressure in Chinese adults.
Methods: 42 participants (aged 18–65 years) were recruited from a rural community in Shaanxi, China. All participants first maintained their normal diet for 3 days, then sequentially ate a low-sodium diet (3.0 g/day NaCl) for 7 days, followed by a high-sodium diet (18.0 g/day NaCl) for 7 days. We assessed their plasma S1P concentrations on the last day of each intervention phase by liquid chromatography-tandem mass spectrometry. We classified the subjects who demonstrated at least a 10% increase in mean arterial pressure upon transitioning from a low-salt to a high-salt diet as salt-sensitive and the others as salt-resistant. Differences in repeated measures were analyzed by repeated-measures analysis of variance.
Results: Plasma S1P levels decreased significantly from the baseline to low-salt diet period and increased from the low-salt to high-salt diet period. We observed this response in both salt-sensitive and salt-resistant individuals. Plasma S1P levels positively correlated with 24-hour urinary sodium excretion, but not 24-hour urinary potassium excretion. In line with plasma S1P level responses to salt intervention, systolic blood pressure (SBP) and mean arterial pressure (MAP) decreased from the baseline to low-salt diet period and increased from the low-salt to high-salt period. SBP positively correlated with plasma S1P and the correlation was stronger in salt-sensitive individuals than that in salt-resistant individuals.
Conclusion: Low-salt dietary intervention decreases plasma S1P levels, whereas high-salt intervention reverses this change and S1P levels positively correlated with SBP in Chinese adults. This provides a high-efficiency and low-cost intervention for plasma S1P levels modulation, with implications for salt-induced blood pressure modulation.
Trial registration: NCT02915315. Registered 27 September 2016, http://www.clinicaltrials.gov
... Recently, it was reported that sphingolipids have a pathological role in hypertension. In human genetic analysis, it was found that sphingolipid metabolism is related to the regulation of blood pressure and hypertension [9]. Plasma lipidomics analysis of spontaneously hypertensive rats (SHR) has also shown that altered sphingolipid signaling is associated with a mechanism to prevent a rise in blood pressure [10]. ...
Recently, lipidomics has revealed that many diseases are highly associated with altered lipid metabolism, as in the case of hypertension affecting serum lipid metabolism. In this study, an LC–MS-based lipidomic approach was used to profile serum lipids in spontaneously hypertensive rats (SHRs) treated with an extract of Acanthopanax sessiliflorus fruits (ASF), to elucidate the serum lipid metabolism alteration by hypertension and the treatment of a drug or ASF. First, UPLC-QTOF/MS profiled a total of 208 lipids from six pooled samples of normal controls, SHR, SHR + 100 mg/kg of drug, and SHR + ASF 200, 400, or 600 mg/kg. These six groups were differentiated by the PCA and sPLS–DA, and 120 lipid species were identified as differentially regulated lipids (DRLs) by ANOVA (p values < 0.05). Second, UPLC–QqQ/MS was used for the target profiling of 120 DRLs from individual samples of the six groups. Using an ANOVA, 67 lipids (38 TGs, 4 DGs, 17 PCs, 2 PEs, and 6 LPCs) were selected as validated DRLs. The mostly altered lipids, such as TG (62:13), TG (60:13), PC (34:4), PC (36:5), and PC (38:2), were decreased in SHR compared to the normal control, and received little by treatment with ASF. These results demonstrated the correlation between hypertension and serum lipid metabolism. Furthermore, both drug and ASF treatment similarly altered the lipid profiles of SHRs. Finally, we found that DRLs have the potential to help us to interpret the lipid metabolism of hypertension.
... A growing number of studies have shown that S1P and its signaling pathway may participate in BP regulation and hypertension [34][35][36]. The effect of S1P on BP is the result of changes in both vascular and heart functions. ...
Background Sphingosine-1-phosphate (S1P), a pleiotropic bioactive sphingolipid metabolite, is involved in various pathophysiological processes,including blood pressure regulation. Salt is a crucial factor for blood pressure modulation,especially in salt-sensitive individuals who may develop earlier, more severe subclinical target organ damage than salt-resistant individuals.However, the relationships among salt intake, circulating S1P levels, and blood pressure changes are unknown. Thus, we conducted this intervention trial to explore the effect of dietary salt intake on plasma S1P levels and examine the relationship between S1P and blood pressure in Chinese adults.
Methods Forty-two participants (aged 18–65 years) were recruited from a rural community in Shaanxi, China. All participants first maintained their normal diet for 3 days, then sequentially ate a low-sodium diet (3.0 g/day NaCl) for 7 days, followed by a high-sodium diet (18.0 g/day NaCl) for 7 days. We assessed their plasma S1P concentrations on the last day of each intervention phase by liquid chromatography–tandem mass spectrometry. We classified the subjects who demonstrated at least a 10% increase in mean arterial pressure upon transitioning from a low-salt to a high-salt diet as salt-sensitive and the others as salt-resistant. Differences in repeated measures were analyzed by repeated-measures analysis of variance.
Results Plasma S1P levels decreased significantly from the baseline to low-salt diet period and increased from the low-salt tohigh-salt diet period. We observed this response in both salt-sensitive and salt-resistant individuals. Plasma S1P levels positively correlated with 24-hour urinary sodium excretion, but not 24-hour urinary potassium excretion. In line with plasma S1P level responses to salt intervention, systolic blood pressure and mean arterial pressure decreased from the baseline to low-salt diet period and increased from the low-salt to high-salt period.Systolic blood pressure positively correlated with plasma S1P; the correlation was stronger in salt-sensitive individuals than in salt-resistant individuals.
Conclusion Low-salt intervention decreased plasma S1P levels, whereas high-salt intervention reversed this changein Chinese adults. This finding provides evidence that salt moderation may be a high-efficiency, low-cost intervention for regulating circulating S1P levels, with implications for salt-induced blood pressure modulation.
Trial registration:
NCT02915315.Registered 27 September,2016,http://www.clinicaltrials.gov
... A growing number of studies have shown that S1P and its signaling pathway may participate in BP regulation and hypertension [34][35][36]. The effect of S1P on BP is the result of changes in both vascular and heart functions. ...
Background: Sphingosine-1-phosphate (S1P), a pleiotropic bioactive sphingolipid metabolite, is involved in various pathophysiological processes,including blood pressure regulation. Salt is a crucial factor for blood pressure modulation,especially in salt-sensitive individuals who may develop earlier, more severe subclinical target organ damage than salt-resistant individuals.However, the relationships among salt intake, circulating S1P levels, and blood pressure changes are unknown. Thus, we conducted this intervention trial to explore the effect of dietary salt intake on plasma S1P levels and examine the relationship between S1P and blood pressure in Chinese adults.
Methods:Forty-two participants (aged 18–65 years) were recruited from a rural community in Shaanxi, China. All participants first maintained their normal diet for 3 days, then sequentially ate a low-sodium diet (3.0 g/day NaCl) for 7 days, followed by a high-sodium diet (18.0 g/day NaCl) for 7 days. We assessed their plasma S1P concentrations on the last day of each intervention phase by liquid chromatography–tandem mass spectrometry. We classified the subjects who demonstrated at least a 10% increase in mean arterial pressure upon transitioning from a low-salt to a high-salt diet as salt-sensitive and the others as salt-resistant. Differences in repeated measures were analyzed by repeated-measures analysis of variance.
Results:Plasma S1P levels decreased significantly from the baseline to low-salt diet period and increased from the low-salt tohigh-salt diet period. We observed this response in both salt-sensitive and salt-resistant individuals. Plasma S1P levels positively correlated with 24-hour urinary sodium excretion, but not 24-hour urinary potassium excretion. In line with plasma S1P level responses to salt intervention, systolic blood pressure and mean arterial pressure decreased from the baseline to low-salt diet period and increased from the low-salt to high-salt period.Systolic blood pressure positively correlated with plasma S1P; the correlation was stronger in salt-sensitive individuals than in salt-resistant individuals.
Conclusion:Low-salt intervention decreased plasma S1P levels, whereas high-salt intervention reversed this changein Chinese adults. This finding provides evidence that salt moderation may be a high-efficiency, low-cost intervention for regulating circulating S1P levels, with implications for salt-induced blood pressure modulation.
Trial registration: NCT02915315.Registered 27 September，2016,http://www.clinicaltrials.gov
