Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease

Abstract

Background Obesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown. Objectives The aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signaling and cardiovascular outcomes. Methods A screen was conducted for metabolites differentially secreted by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis (n = 48), and these metabolites were then linked with dysregulated vascular redox signaling in 633 patients undergoing coronary bypass surgery. The underlying mechanisms were explored in human aortic endothelial cells, and their clinical value was tested against hard clinical endpoints. Results Because ThAT volume was associated significantly with arterial oxidative stress, there were significant differences in sphingolipid secretion between ThAT and subcutaneous AT, with C16:0-ceramide and derivatives being the most abundant species released within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion was significantly associated with reduced endothelial nitric oxide bioavailability and increased superoxide generated in human vessels. Circulating C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular redox signaling, and increased systemic inflammation in 633 patients with atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma C16:0-ceramide and its glycosylated derivative were independently related with increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 SD). In a randomized controlled clinical trial, 1-year treatment of obese patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects. Conclusions These results demonstrate for the first time in humans that AT-derived ceramides are modifiable regulators of vascular redox state in obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. (The Interaction Between Appetite Hormones; NCT02094183 )

Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride

“…Interestingly, in the present study, subjects with a former myocardial infarction were found having increased levels of glycoceramides at baseline, lending support to the notion of an association between ceramides and atherosclerosis. Recently, it was demonstrated that fat-secreted ceramides are modifiable regulators of vascular redox state with a direct impact on CV mortality in people with atherosclerosis and that liraglutide was a potential drug target to decrease the risk [ 10 ]. It was also recently found that accumulation of ceramides associates with de novo lipogenesis and insulin resistance leading to low-grade inflammation [ 33 ], which, in turn, is suggested to increase the risk of T2D and CV disease [ 34 ].…”

“…MS data processing was performed using open-source software MZmine 2.53 [ 10 ]. Quantitation of the following metabolites (aspartic acid, glutamic acid, isoleucine, methionine, fumaric acid, malic acid, leucine, valine, glycerol-3-phosphate, alanine, threonine, 3-hydroxybutyric acid, isocitric acid, arachidonic acid, glutamine, lactic acid, linoleic acid, oleic acid, palmitic acid, stearic acid and lysine, beta-muricholic acid (b-MCA), cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), glycohyocholic acid (GHCA), glycohyodeoxycholic acid (GHDCA), glycolitocholic acid (GLCA), glycoursodeoxycholic acid (GUDCA), hyocholic acid (HCA), hyodeoxycholic acid (HDCA), lithocholic acid (LCA), tauro-alpha/beta-muricholic acid (Ta,bMCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), Taurodeoxycholic acid (TDCA) taurodehydrocholic acid (TDHCA), trihydroxycholestanoic acid (THCA), taurohyodeoxycholic acid (THDCA), taurolitocholic acid (TLCA), tauroursodeoxycholic acid (TUDCA), tauro-omega-muricholic acid (TwMCA), ursodeoxycholic acid (UDCA), omega/alpha-muricholic acid (w/a-MCA) was done using authentic standards at six different concentrations, other metabolites were determined semi-quantitatively.…”

“…Beside the reduction in weight and glucose levels of liraglutide treatment, there are several indirect actions reported regarding heart function and the vessel evoked by activation of GLP-1 receptors (GLP-1 R) [ 8 , 9 ]. These actions may include alterations in the substrate of fatty acids and glucose delivered to the heart and to the liver, altering vascular redox state, which may be a target for GLP-1 RAs [ 10 ].…”

How Ceramides Orchestrate Cardiometabolic Health—An Ode to Physically Active Living

“…From a cardiovascular perspective, ceramides located at the surface of LDL drive their transcytosis through the endothelium and uptake into macrophages, which results in foam cell formation, vascular inflammation, and atherosclerosis [40][41][42]. Thoracic adipose tissue of obese individuals secretes a particular ceramide species, named Cer (18:1;2/16:0), which acts on endothelial cells to reduce vasodilatation, induce inflammation, oxidative stress, and finally increase risk of cardiovascular death [55]. Again, circulating long-chain ceramides, such as Cer (18:1;2/16:0), Cer (18:1;2/18:0) and Cer (18:1;2/24:1), seem to be the species most frequently associated with cardiovascular morbidity and mortality [10,31,56].…”

Mitochondrial Dynamics: Pathogenesis and Therapeutic Targets of Vascular Diseases

“…Cardiovascular disease (CVD) is the leading cause of death worldwide ( 1 ). Vascular diseases, particularly atherosclerosis, are initiated at an early stage in life and remain asymptomatic for a long period until they reach advanced stages ( 2 ). Among vascular diseases, atherosclerosis is a pathologic process of lipid accumulation, scarring, and inflammation in the vascular wall, particularly the subendothelial (intimal) space of arteries, which leads to vascular wall thickening, luminal stenosis, and calcification ( 3 ).…”