Plasma Ceramides Research Articles

Association between the plasma ceramide and coronary microvascular resistance

BackgroundPlasma ceramide plays a potentially significant role in the pathogenesis of coronary microvascular dysfunction. However, the relationship between plasma ceramide and coronary microvascular resistance in patients remains unclear. This study aimed to evaluate the association between plasma ceramide levels, as well as their distinct ratios, and coronary microvascular resistance.MethodsThis single-center observational study retrospectively enrolled patients who underwent both ceramide measurement and coronary angiography during hospitalization. The microvascular resistance of the coronary arteries was assessed in all patients using the angiography-derived index of microcirculatory resistance (Angio-IMR). The cumulative coronary microvascular resistance was calculated by summing the microvascular resistance of the three main coronary arteries. Multiple linear and logistic regression analyses were employed to evaluate the relationship between plasma ceramide and cumulative coronary microvascular resistance. Restricted cubic spline (RCS) analysis was conducted to investigate the association between plasma ceramide levels and cumulative coronary microvascular resistance. Receiver operating characteristic (ROC) curves were employed to evaluate the predictive value of plasma ceramide for coronary microvascular resistance. Additionally, subgroup analyses and interaction tests were performed.ResultsA total of 225 patients were included in this study, with a median cumulative coronary microvascular resistance of 48.04 (40.32–56.73). After adjusting for potential confounding factors, both plasma 16:0 ceramide and the 16:0/24:0 ceramide ratio were positively associated with cumulative coronary microvascular resistance [standardized β ± standard error: 75.05 ± 8.46 (P < 0.001) and 91.72 ± 20.41 (P < 0.001), respectively]. Similar independent associations were observed in predicting high cumulative microvascular resistance [β = 8.03 ± 1.91 (P < 0.001) and 9.98 ± 3.88 (P = 0.010), respectively]. Additionally, a significant nonlinear relationship was observed between plasma 16:0 ceramide, the 16:0/24:0 ceramide ratio, and cumulative coronary microvascular resistance (P for nonlinear < 0.05). The ROC analysis revealed that the optimal cut-off for plasma 16:0 ceramide is 0.178 µmol/L, with a specificity of 57.1% and a sensitivity of 91.2%. For the 16:0/24:0 ceramide ratio, the optimal cut-off is 0.072, yielding a specificity of 73.2% and a sensitivity of 54.9%. Subgroup analysis indicated that the association between plasma ceramide and coronary microvascular resistance was trending toward non-significance in patients with acute coronary syndrome (ACS).ConclusionsA significant nonlinear relationship exists between plasma ceramide and coronary microvascular resistance, which holds important clinical implications for the risk stratification of coronary microvascular disease. New insights into the potential effects of ceramides enhance our understanding of the complex mechanisms underlying coronary microvascular disease and warrant further investigation in a broader population.Graphical abstract

Inhibition of ceramide de novo synthesis mitigates atherosclerosis

Abstract Background Atherosclerosis is the primary underlying cause of cardiovascular disease. Plasma ceramides are positively correlated with an increased risk of major adverse cardiovascular events and serve as an alternative biomarker for cardiovascular disease. Importantly, ceramide levels are notably higher within atherosclerotic plaques. Therefore, inhibiting the ceramide de novo synthesis pathway in the plaques may serve as a potential therapeutic intervention for atherosclerosis. Purpose We aim to assess the therapeutic efficacy of a nano-formulation of myriocin, a targeted inhibitor of serine-palmitoyl transferase, the key enzyme in ceramide de novo synthesis, in treating atherosclerosis. Methods Myriocin was encapsulated within the hydrophobic core of lipid-based nanoparticles specifically designed for this study. Male and female ApoE-/- mice, subjected to an 8-week high-fat diet regimen, received either myriocin nanoparticles (treatment group) or empty nanoparticles (control group) intravenously once a week for 4 weeks at a dose of 1.3 mg/kg body weight while still on the high-fat diet. At the study endpoint, whole aortas were harvested and subjected to Oil Red O staining to quantify the total lesion area. Histological staining was performed on serial sections of the aortic root to analyze the cellular composition within the plaques. Plasma samples were collected for total cholesterol measurement and lipidomic analysis. Results Upon intravenous administration, myriocin nanoparticles exhibited preferential accumulation in atherosclerotic plaques. Compared to control mice, those treated with myriocin nanoparticles exhibited a 58.7% reduction in total lesion area in male ApoE-/- mice and a 64.6% reduction in female ApoE-/- mice (p&amp;lt;0.0001). Consistently, the lesion areas in the aortic root were also reduced in the treated mice. Notably, myriocin nanoparticles enhanced collagen and alpha-smooth muscle content, while reducing macrophages and neutral lipids within the plaques, leading to a reduced plaque vulnerability index and preventing rupture events. TUNEL staining revealed reduced cellular apoptosis in the atherosclerotic plaques, resulting in a smaller necrotic area in the treated mice. In vitro experiments demonstrated that myriocin nanoparticles effectively inhibited lipopolysaccharide-induced inflammatory response and oxidative stress in bone marrow-derived macrophages. Furthermore, myriocin nanoparticles restored the gene expression of enzymes involved in the fatty acid beta-oxidation pathway, such as ACOX1 and CPT1A, in foam cells. Conclusion Using myriocin nanoparticles to inhibit excessive ceramide production due to inflammation reduces inflammation, and ROS production, while restoring fatty acid beta-oxidation in macrophages. This approach emerges as an effective strategy for targeting ceramide de novo synthesis within atherosclerotic plaques, thereby mitigating atherosclerosis progression and improving plaque stability.

ASO Visual Abstract: Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma.

ASO Visual Abstract: Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma.

Plasma sphingomyelin levels were negatively correlated with ferritin levels in splenectomized thalassemia patients

Abstract Beta thalassemia results from decreased production of beta chains due to either mutations or deletions in the beta-globin gene, leading to impaired production of hemoglobin A. Thalassemia patients take frequent blood transfusions to compensate for hemolytic anemia and iron overload. Iron overload is monitored by serum ferritin levels in these patients. Extra-medullary hematopoiesis in beta thalassemia major leads to hypersplenism which often necessitates splenectomy to increase red cell life span and decrease transfusion need. Sphingomyelin is the second most abundant phospholipid in human plasma after phosphatidylcholine. In contrast to the well-defined roles of sphingolipids in cell membranes, their possible physiological role in lipoprotein metabolism has recently gained attention. Increased circulating levels of sphingomyelins and ceramides were observed in obesity, diabetes, and cardiovascular diseases. Although lipid abnormalities such as hypocholesterolemia and relatively increased triglycerides were reported in beta-thalassemia patients, there is no study investigating sphingolipid levels in thalassemia. Therefore, we investigate certain long chain and very long chain sphingomyelins and ceramides in beta-thalassemia patients who are under routine follow-up in our hospital. Thalassemia major patients who applied to the hospital for regular blood transfusion and gave consent were included in the study. Blood samples were obtained before transfusion. Plasma sphingomyelin (C16, C18 and C24) and ceramide (C16, C18, C20, C22, C24) species were measured by triple quadruple LC-ESI-MS/MS (Shimadzu, Japan). D-erythrosphingosine-D9 (Matreya) was used as an internal standard, all other lipid standards were from Avanti. Body iron stores of the patients were monitored by serum ferritin levels. A total of thirty patients were included in the study. All patients typically received regular erythrocyte suspension transfusions every three weeks and continuous oral iron chelation therapy. Twenty of the patients had a previous splenectomy. The mean age was 34.5 ±8.1 years in the splenectomy group and 32.8 ±8 years in the group without splenectomy. Mean ferritin levels were not different between the groups, being 1073.2±563.5 µg/L in splenectomy and 1709 ±1660.4 µg/L in non-splenectomy groups. All measured sphingolipid levels were similar between splenectomy and non-splenectomy groups. When correlation analysis was performed between measured sphingolipid and ferritin levels, significant negative correlations were found between sphingomyelin C16 (r= -0.591 p&amp;lt;0.006) and C18 (r= -0.594 p&amp;lt;0.006) with ferritin levels in the splenectomy group. However, this negative correlation was absent in the non-splenectomy group. In conclusion, we found that iron overload is associated with lower plasma sphingomyelin levels in splenectomized thalassemia patients. We have been working on the lipidomic analysis of the plasma and erythrocytes of thalassemia patients and other hemolytic anemias. The results may further help to get a better picture of lipid metabolism in thalassemia.

Phosphatidic acid is involved in regulation of autophagy in neurons in vitro and in vivo.

Major depressive disorder (MDD) is a common and severe psychiatric disease, which does not only lead to variety of neuropsychiatric symptoms, but unfortunately in a relatively large proportion of cases also to suicide. The pathogenesis of MDD still requires definition. We have previously shown that ceramide is increased in the blood plasma of patients with MDD. In mouse models of MDD, which are induced by treatment with corticosterone or application of chronic unpredictable stress, increased blood plasma ceramide also increased and caused an inhibition of phospholipase D in endothelial cells of the hippocampus and reduced phosphatidic acid levels in the hippocampus. Here, we demonstrated that corticosterone treatment of PC12 cells resulted in reduced cellular autophagy, which is corrected by treatment with phosphatidic acid. In vivo, treatment of mice with corticosterone or chronic unpredictable stress also reduced autophagy in hippocampus neurons. Autophagy was normalized upon i.v. injection of phosphatidic acid in these mouse models of MDD. In an attempt to identify targets of phosphatidic acid in neurons, we demonstrated that corticosterone reduced levels of the ganglioside GM1 in PC-12 cells and the hippocampus of mice, which were normalized by treatment of cells or i.v. injection of mice with phosphatidic acid. GM1 application also normalized autophagy in cultured neurons. Phosphatidic acid and GM1 corrected stress-induced alterations in behavior, i.e., mainly anxiety and anhedonia, in experimental MDD in mice. Our data suggest that phosphatidic acid may regulate via GM1 autophagy in neurons.

Exploratory Analysis of the Association Between Plasma Ceramide Alterations and Cognitive Dysfunction in Parkinson's Disease.

Prior research has underscored the importance of sphingolipid metabolism in Parkinson's disease (PD) pathogenesis. Our objective was to explore the associations between plasma ceramide levels and PD patients with cognitive dysfunction (PD-CD). We enrolled two study populations from Eastern China and the Parkinson's Progression Markers Initiative (PPMI), comprising 290 (100 HCs, 160 PDs, and 30 MSAs) and 429 (125 HCs and 304 PDs) participants, respectively. The plasma levels of ceramides (Cer 16:0, Cer 18:0, Cer 24:0, and Cer 24:1) were tested via HPLC-MS/MS analysis. Compared with those in the HC group, the plasma levels of Cer 18:0, Cer 24:1, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were higher in both the PD and MSA groups. Significant differences in the plasma levels of Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were observed among the PD-NC (PD with normal cognition), PD-MCI (PD with mild cognitive impairment), and PDD (PD dementia) groups, with the PDD group exhibiting the highest levels. PD patients with higher baseline levels of plasma ceramides (specifically, Cer 18:0, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0) demonstrated accelerated cognitive decline compared with individuals who had lower baseline plasma ceramide levels during the 5-year follow-up period. A biomarker panel including Cer 18:0/Cer 24:0 and Cer 24:1/Cer 24:0 could effectively differentiate PD-CD from PD-NC with notable diagnostic accuracy. Our results indicate that plasma ceramide levels could potentially be used as diagnostic biomarkers for PD-CD.

Plasma C24:0 ceramide impairs adipose tissue remodeling and promotes liver steatosis and glucose imbalance in offspring of rats

Fetal programming by exposure to high-energy diets increases the susceptibility to type 2 diabetes mellitus (T2DM2) in the offspring. Glucose imbalance during fetal programming might be associated to still unknown selective lipid species and their characterization might be beneficial for T2DM diagnosis and treatment. We aim to characterize the effect of the lipid specie, C24:0 ceramide, on glucose imbalance and metabolic impairment in cellular and murine models. A lipidomic analysis identified accumulation of C24:0 ceramide in plasma of offspring rats exposed to high-energy diets during fetal programing, as well as in obese-T2DM subjects. In vitro experiments in 3T3L-1, hMSC and HUH7 cells and in in vivo models of Wistar rats and C57BL/6 mice demonstrated that C24:0 ceramide disrupted glucose balance, and differentiation and lipid accumulation in adipocytes, whereas promoted liver steatosis. Mechanistically, C24:0 ceramide impaired mitochondrial fatty acid oxidation in adipocytes and hepatic cells, tentatively by favoring reactive oxygen species accumulation and calcium overload in the mitochondria; and also, activates endoplasmic reticulum (ER) stress in hepatocytes. We propose that C24:0 ceramide accumulation in the offspring followed a prenatal diet exposure, impair lipid allocation into adipocytes and enhances liver steatosis associated to mitochondrial dysfunction and ER stress, leading to glucose imbalance.

Plasma Ceramides and Risk of Cardiovascular Events in CKD

Plasma Ceramides and Risk of Cardiovascular Events in CKD

Plasma Ceramides and CKD Progression in Type 2 Diabetes

Plasma Ceramides and CKD Progression in Type 2 Diabetes

Immunometabolic Chaos in Septic Shock.

Septic shock is associated with over 40% mortality. The immune response in septic shock is tightly regulated by cellular metabolism and transitions from early hyper-inflammation to later hypo-inflammation. Patients are susceptible to secondary infections during hypo-inflammation. The magnitude of the metabolic dysregulation and the effect of plasma metabolites on the circulating immune cells in septic shock are not reported. We hypothesized that the accumulated plasma metabolites affect the immune response in septic shock during hypo-inflammation. Our study took a unique approach. Using peripheral blood from adult septic shock patients and healthy controls, we studied: 1. Whole blood stimulation ± E. Coli lipopolysaccharide (LPS: endotoxin) to analyze plasma TNF protein, and 2. Plasma metabolomic profile by Metabolon. Inc. 3. We exposed peripheral blood mononuclear cells (PBMCs) from healthy controls to commercially available carbohydrate, amino acid, and fatty acid metabolites and studied the response to LPS. We report that: 1. The whole blood stimulation of the healthy control group showed a significantly upregulated TNF protein, while the septic shock group remained endotoxin tolerant, a biomarker for hypo-inflammation. 2. A significant accumulation of carbohydrate, amino acid, fatty acid, ceramide, sphingomyelin, and TCA cycle pathway metabolites in septic shock plasma. 3. In vitro exposure to five metabolites repressed while two metabolites upregulated the inflammatory response of PBMCs to LPS. We conclude that the endotoxin-tolerant phenotype of septic shock is associated with a simultaneous accumulation of plasma metabolites from multiple metabolic pathways, and these metabolites fundamentally influence the immune response profile of circulating cells.

Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma

Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma

Plasma ceramides as biomarkers for microvascular disease and clinical outcomes in diabetes and myocardial infarction

BackgroundCeramides have recently been identified as novel biomarkers associated with diabetes mellitus (DM) and major adverse cardiac and cerebrovascular events (MACCE). This study aims to explore their utility in diagnosing microvascular disease.MethodsThis study prospectively enrolled 309 patients from 2018 to 2020 into three groups: healthy controls (Group 1, N = 51), DM patients without acute myocardial infarction (AMI) (Group 2, N = 150), and DM patients with AMI (Group 3, N = 108). We assessed outcomes using stress perfusion cardiac magnetic resonance (CMR) imaging for coronary microvascular disease (CMD) (Outcome 1), retinography for retinal microvascular disease (RMD) (Outcome 2), both CMD and RMD (Outcome 3), and absence of microvascular disease (w/o MD) (outcome 4). We evaluated the classification performance of ceramides using receiver operating characteristic (ROC) analysis and multiple logistic regression. 11-ceramide panel previously identified by our research group as related to macrovascular disease were used.ResultsAverage glycated hemoglobin (HbA1c) values were 5.1% in Group 1, 8.3% in Group 2, and 7.6% in Group 3. Within the cohort, CMD was present in 59.5% of patients, RMD in 25.8%, both CMD and RMD in 18.8%, and w/o MD in 38.5%. The AUC values for the reference ceramide ratios were as follows: CMD at 0.66 (p = 0.012), RMD at 0.61 (p = 0.248), CMD & RMD at 0.64 (p = 0.282), and w/o MD at 0.67 (p = 0.010). In contrast, the AUC values using 11-ceramide panel showed significant improvement in the outcomes prediction: CMD at 0.81 (p = 0.001), RMD at 0.73 (p = 0.010), CMD & RMD at 0.73 (p = 0.04), and w/o MD at 0.83 (p = 0.010). Additionally, the plasma concentration of C14.0 was notably higher in the w/o MD group (p < 0.001).ConclusionsPlasma ceramides serve as potential predictors for health status and microvascular disease phenotypes in diabetic patients.

Sphingolipid metabolites as potential circulating biomarkers for sarcopenia in men.

Sarcopenia is an age-related progressive loss of muscle mass and function. Sarcopenia is a multifactorial disorder, including metabolic disturbance; therefore, metabolites may be used as circulating biomarkers for sarcopenia. We aimed to investigate potential biomarkers of sarcopenia using metabolomics. After non-targeted metabolome profiling of plasma from mice of an aging mouse model of sarcopenia, sphingolipid metabolites and muscle cells from the animal model were evaluated using targeted metabolome profiling. The associations between sphingolipid metabolites identified from mouse and cell studies and sarcopenia status were assessed in men in an age-matched discovery (72 cases and 72 controls) and validation (36 cases and 128 controls) cohort; women with sarcopenia (36 cases and 36 controls) were also included as a discovery cohort. Both non-targeted and targeted metabolome profiling in the experimental studies showed an association between sphingolipid metabolites, including ceramides (CERs) and sphingomyelins (SMs), and sarcopenia. Plasma SM (16:0), CER (24:1), and SM (24:1) levels in men with sarcopenia were significantly higher in the discovery cohort than in the controls (all P<0.05). There were no significant differences in plasma sphingolipid levels for women with or without sarcopenia. In men in the discovery cohort, an area under the receiver-operating characteristic curve (AUROC) of SM (16:0) for low muscle strength and low muscle mass was 0.600 (95% confidence interval [CI]: 0.501-0.699) and 0.647 (95% CI: 0.557-0.737). The AUROC (95% CI) of CER (24:1) and SM (24:1) for low muscle mass in men was 0.669 (95% CI: 0.581-0.757) and 0.670 (95% CI: 0.582-0.759), respectively. Using a regression equation combining CER (24:1) and SM (16:0) levels, a sphingolipid (SphL) score was calculated; an AUROC of the SphL score for sarcopenia was 0.712 (95% CI: 0.626-0.798). The addition of the SphL score to HGS significantly improved the AUC from 0.646 (95% CI: 0.575-0.717; HGS only) to 0.751 (95% CI: 0.671-0.831, P=0.002; HGS+SphL) in the discovery cohort. The predictive ability of the SphL score for sarcopenia was confirmed in the validation cohort (AUROC=0.695, 95% CI: 0.591-0.799). SM (16:0), reflecting low muscle strength, and CER (24:1) and SM (16:0), reflecting low muscle mass, are potential circulating biomarkers for sarcopenia in men. Further research on sphingolipid metabolites is required to confirm these results and provide additional insights into the metabolomic changes relevant to the pathogenesis and diagnosis of sarcopenia.

Basal and post-stress ceramide-based risk score CERT1 predicts all-cause mortality and nonfatal myocardial infarction in patients with suspected or established coronary artery disease undergoing stress myocardial perfusion scintigraphy

Background and aimWe examined whether a plasma ceramide-based risk score (CERT1 score), a newly proposed tool for cardiovascular risk prediction, is associated with an increased risk of all-cause mortality and nonfatal myocardial infarction in patients with suspected or known coronary artery disease (CAD). Methods and resultsWe studied 167 ambulatory patients who consecutively underwent stress myocardial perfusion scintigraphy (MPS) for clinical reasons in 2017 (at baseline) and then followed for a median of 6 years (inter-quartile range: 4.7–6.6 years). For the calculation of the CERT1 score, both before and after stress MPS, we measured three specific plasma ceramide concentrations [Cer(d18:1/16:0), Cer(d18:1/18:0) and Cer(d18:1/24:1)] and their ratio to Cer(d18:1/24:0) using a targeted liquid chromatography-tandem mass spectrometry assay. The primary outcome of the study was a composite of all-cause mortality or nonfatal myocardial infarction. During a median of 6 years, a total of 50 events occurred (26 all-cause deaths and 24 nonfatal myocardial infarctions). There was a significant association between pre-stress CERT1 risk categories (high vs. low risk) at baseline and the risk of developing the primary composite outcome (unadjusted HR 1.78, 95% CI 1.02–3.14). This risk remained significant after adjustment for age, sex, smoking, diabetes, pre-existing CAD, left ventricular ejection fraction, and stress-induced inducible myocardial ischemia on MPS (adjusted HR 2.28, 95% CI 1.17–4.41, p = 0.015). Almost identical results were observed for post-stress CERT1 risk categories. ConclusionsPre-stress and post-stress CERT1 high-risk categories at baseline were strongly associated with an increased long-term risk of all-cause mortality or nonfatal myocardial infarction in patients with suspected or established CAD.

Ceramides-Emerging Biomarkers of Lipotoxicity in Obesity, Diabetes, Cardiovascular Diseases, and Inflammation.

Abnormalities in lipid homeostasis have been associated with many human diseases, and the interrelation between lipotoxicity and cellular dysfunction has received significant attention in the past two decades. Ceramides (Cers) are bioactive lipid molecules that serve as precursors of all complex sphingolipids. Besides their function as structural components in cell and mitochondrial membranes, Cers play a significant role as key mediators in cell metabolism and are involved in numerous cellular processes, such as proliferation, differentiation, inflammation, and induction of apoptosis. The accumulation of various ceramides in tissues causes metabolic and cellular disturbances. Recent studies suggest that Cer lipotoxicity has an important role in obesity, metabolic syndrome, type 2 diabetes, atherosclerosis, and cardiovascular diseases (CVDs). In humans, elevated plasma ceramide levels are associated with insulin resistance and impaired cardiovascular and metabolic health. In this review, we summarize the role of ceramides as key mediators of lipotoxicity in obesity, diabetes, cardiovascular diseases, and inflammation and their potential as a promising diagnostic tool.

Sphingolipid Metabolism Is Associated with Cardiac Dyssynchrony in Patients with Acute Myocardial Infarction.

Sphingolipids are a class of complex and bioactive lipids that are involved in the pathological processes of cardiovascular disease. Fabry disease is an X-linked storage disorder that results in the pathological accumulation of glycosphingolipids in body fluids and the heart. Cardiac dyssynchrony is observed in patients with Fabry disease and left ventricular (LV) hypertrophy. However, little information is available on the relationship between plasma sphingolipid metabolites and LV remodelling after acute myocardial infarction (AMI). The purpose of this study was to assess whether the baseline plasma sphingomyelin/acid ceramidase (aCD) ratio predicts LV dyssynchrony at 6M after AMI. A total of 62 patients with AMI undergoing primary angioplasty were recruited. Plasma aCD and sphingomyelin were measured prior to primary angioplasty. Three-dimensional echocardiographic measurements of the systolic dyssynchrony index (SDI) were performed at baseline and 6 months of follow-up. The patients were divided into three groups according to the level of aCD and sphingomyelin above or below the median. Group 1 denotes lower aCD and lower sphingomyelin; Group 3 denotes higher aCD and higher sphingomyelin. Group 2 represents different categories of patients with aCD and sphingomyelin. Trend analysis showed a significant increase in the SDI from Group 1 to Group 3. Logistic regression analysis showed that the sphingomyelin/aCD ratio was a significant predictor of a worsening SDI at 6 months. AMI patients with high baseline plasma sphingomyelin/aCD ratios had a significantly increased SDI at six months. The sphingomyelin/aCD ratio can be considered as a surrogate marker of plasma ceramide load or inefficient ceramide metabolism. Plasma sphingolipid pathway metabolism may be a new biomarker for therapeutic intervention to prevent adverse remodelling after MI.

Ying and Yang of Ceramide in the Vascular Endothelium.

Ceramides, a group of biologically active sphingolipids, have been described as the new cholesterol given strong evidence linking high plasma ceramide with endothelial damage, risk for early adverse cardiovascular events, and development of cardiometabolic disease. This relationship has sparked great interest in investigating therapeutic targets with the goal of suppressing ceramide formation. However, the growing data challenge this paradigm of ceramide as solely eliciting detrimental effects to the cardiovascular system. Studies show that ceramides are necessary for maintaining proper endothelial redox states, mechanosensation, and membrane integrity. Recent work in preclinical models and isolated human microvessels highlights that the loss of ceramide formation can in fact propagate vascular endothelial dysfunction. Here, we delve into these conflicting findings to evaluate how ceramide may be capable of exerting both beneficial and damaging effects within the vascular endothelium. We propose a unifying theory that while basal levels of ceramide in response to physiological stimuli are required for the production of vasoprotective metabolites such as S1P (sphingosine-1-phosphate), the chronic accumulation of ceramide can promote activation of pro-oxidative stress pathways in endothelial cells. Clinically, the evidence discussed here highlights the potential challenges associated with therapeutic suppression of ceramide formation as a means of reducing cardiovascular disease risk.

Oxidative stress and plasma ceramides in broiler chickens.

The selection for rapid growth in chickens has rendered meat-type (broiler) chickens susceptible to develop metabolic syndrome and thus inflammation. The sphingolipid ceramide has been linked as a marker of oxidative stress in mammals, however, the relationship between sphingolipid ceramide supply and oxidative stress in broiler chickens has not been investigated. Therefore, we employed a lipidomic approach to investigate the changes in circulating sphingolipid ceramides in context of allopurinol-induced oxidative stress in birds. Day zero hatched chicks (n = 60) were equally divided into six groups; an unsupplemented control, an allopurinol group (25mg/kg body weight), a conjugated linoleic acid (CLA) group where half of the oil used in the control diet was substituted for a CLA oil mixture, a CLA and an allopurinol group utilizing the same dose of CLA and allopurinol, a berberine (BRB) group consisting of berberine supplementation (200mg/kg feed), and a BRB and allopurinol group, utilizing the same dose of BRB and allopurinol. Conjugated linoleic acid and berberine were utilized to potentially enhance antioxidant activity and suppress the oxidative stress induced by allopurinol treatment. Body weight, plasma uric acid, nonesterified fatty acids (NEFA) and sphingolipid ceramides were quantified. Allopurinol induced an inflammatory state as measured by a significant reduction in plasma uric acid - an antioxidant in birds as well as a metabolic waste product. Results showed that both total and saturated sphingolipid ceramides declined (p < 0.05) with age in unsupplemented chicks, although plasma ceramides C16:0 and 18:0 increased in concentration over the study period. Simple total and saturated sphingolipid ceremide's were further decreased (p < 0.05) with allopurinol supplementation, however, this may be an indirect consequence of inducing an inflammatory state. Neither CLA or BRB were able to significantly attenuate the decline. The administration of allopurinol specifically targets the liver which in birds, is the primary organ for fatty acids synthesis. For this reason, sphingolipid ceramide production might have been unwittingly affected by the addition of allopurinol.

Circulating Sphingolipids and All-Cause Mortality: The Strong Heart Family Study.

A growing body of research indicates that associations of ceramides and sphingomyelins with mortality depend on the chain length of the fatty acid acylated to the backbone sphingoid base. We examined associations of 8 ceramide and sphingomyelin species with mortality among an American Indian population. The analysis comprised 2688 participants from the SHFS (Strong Heart Family Study). Plasma ceramide and sphingomyelin species carrying long-chain (ie, 16:0) and very-long-chain (ie, 20:0, 22:0, 24:0) saturated fatty acids were measured by sequential liquid chromatography and mass spectroscopy using samples from 2001 to 2003. Participants were followed for 18.8 years (2001-2020). Associations of ceramides and sphingomyelins with mortality were assessed using Cox models. The mean age of participants was 40.8 years. There were 574 deaths during a median 17.4-year follow-up. Ceramides and sphingomyelins carrying fatty acid 16:0 were positively associated with mortality. Ceramides and sphingomyelins carrying longer fatty acids were inversely associated with mortality. Per SD difference in each ceramide and sphingomyelin species, hazard ratios for death were: 1.68 (95% CI, 1.44-1.96) for ceramide-16 (Cer-16), 0.82 (95% CI, 0.71-0.95) for Cer-20, 0.60 (95% CI, 0.51-0.70) for Cer-22, 0.67 (95% CI, 0.56-0.79) for Cer-24, 1.80 (95% CI-1.57, 2.05) for sphingomyelin-16 (SM-16), 0.54 (95% CI, 0.47-0.62) for SM-20, 0.50 (95% CI, 0.44-0.57) for SM-22, and 0.59 (95% CI, 0.52-0.67) for SM-24. The direction/magnitude of associations of ceramides and sphingomyelins with mortality differs according to the length of the fatty acid acylated to the backbone sphingoid base. URL: https://www.clinicatrials.gov; Unique identifier: NCT00005134.

The relationship between ceramide profile and residual inflammatory risk in patients with coronary artery disease: Insights from an prospective study

BackgroundAlthough progress has been made in managing cholesterol, targeting inflammation is essential for further reducing cardiovascular risk, as CVDs remain the leading cause of death globally. This study aimed to explore the association between plasma ceramide levels and residual inflammatory risk in patients with CAD. MethodsA cross-sectional observational design was adopted using data from a secondary analysis of a multicenter prospective cohort study in China. Patients were categorized into two groups based on a hs-CRP level of 2.0mg/L. Plasma ceramide levels were measured using the LC-MS/MS system. By collecting and statistically analyzing patient demographic and clinical characteristics, differences were compared between the low residual inflammatory risk group (Low RIR) and the high residual inflammatory risk group (High RIR). Multivariate logistic regression analysis was used to assess the interaction of plasma ceramides with high residual inflammation risk. ResultsA total of 778 patients with confirmed CAD were included in the study. Compared to the Low RIR, Cer (d18:1/16:0), Cer (d18:1/18:0), Cer (d18:1/20:0), Cer (d18:1/22:0), Cer (d18:1/24:0), and Cer (d18:1/24:1), were significantly elevated in the High RIR group. Spearman correlation analysis indicated that Cer (d18:1/16:0) levels were positively correlated with hsCRP. Further multivariable logistic regression analysis revealed that Cer (d18:1/16:0) was a significant independent indicator of high RIR beyond conventional cardiovascular risk factors. ConclusionThis study found a significant association between specific plasma ceramide Cer (d18:1/16:0) and high residual inflammatory risk in CAD patients, suggesting it could be an important inflammatory biomarker in the management of cardiovascular diseases.