Sphingolipids and Atherosclerosis: The Dual Role of Ceramide and Sphingosine-1-Phosphate

Abstract

Sphingolipids are bioactive molecules that play either pro- and anti-atherogenic roles in the formation and maturation of atherosclerotic plaques. Among SLs, ceramide and sphingosine-1-phosphate showed antithetic properties in regulating various molecular mechanisms and have emerged as novel potential targets for regulating the development of atherosclerosis. In particular, maintaining the balance of the so-called ceramide/S1P rheostat is important to prevent the occurrence of endothelial dysfunction, which is the trigger for the entire atherosclerotic process and is strongly associated with increased oxidative stress. In addition, these two sphingolipids, together with many other sphingolipid mediators, are directly involved in the progression of atherogenesis and the formation of atherosclerotic plaques by promoting the oxidation of low-density lipoproteins (LDL) and influencing the vascular smooth muscle cell phenotype. The modulation of ceramide and S1P levels may therefore allow the development of new antioxidant therapies that can prevent or at least impair the onset of atherogenesis, which would ultimately improve the quality of life of patients with coronary artery disease and significantly reduce their mortality.

Naringenin Inhibits Acid Sphingomyelinase-Mediated Membrane Raft Clustering to Reduce NADPH Oxidase Activation and Vascular Inflammation

“…Ceramide is a central molecule of sphingolipid metabolism composed of sphingosine and a fatty acid chain. In addition to being a component of cell membranes, ceramide functions as a second messenger to regulate numerous cellular processes, including apoptosis, proliferation, migration, and autophagy . Ceramide is elevated in numerous pathological conditions, such as neurodegenerative disorders, endothelial dysfunction, cancer, and bowel inflammation, and contributes to these pathological processes. − Therefore, it is interesting to further investigate ceramide metabolism regulation by naringenin, which will help to fully understand the biological role of naringenin.…”

Ceramides: a potential cardiovascular biomarker in young adult childhood cancer survivors?

“…C16:0 has been implicated as one of the key drivers of atherosclerosis by its uptake into the endothelial cell mitochondria membranes where they form channels and cause cytochrome-c release and induction of apoptosis. 49 Further, ceramides cause endothelial dysfunction by decreasing nitric oxide (NO) production and by increasing NO breakdown by the formation of reactive oxygen species. 31 These data suggest that a combination of elevated circulating levels of these ceramides, perhaps driven by C16:0, might cause an increase in vascular tone coincident with increased arterial stiffness.…”

Circulating Sphingolipids and Glucose Homeostasis: An Update

“…This observation led the group of Summers to suggest that circulating ceramides, like cholesterol, could be used as biomarkers that predict cardiovascular events [ 48 ]. In addition, ceramide metabolism plays a central pro-atherogenic role in both the formation and maturation of atherosclerotic plaques through the regulation of oxidative stress [ 61 ]. Ceramide mediates insulin resistance through several mechanisms, including oxidative stress [ 62 ].…”