Bioactive Sphingolipids as Major Regulators of Coronary Artery Disease

Abstract

Atherosclerosis is the deposition of plaque in the main arteries. It is an inflammatory condition involving the accumulation of macrophages and various lipids (low-density lipoprotein [LDL] cholesterol, ceramide, S1P). Moreover, endothelial cells, macrophages, leukocytes, and smooth muscle cells are the major players in the atherogenic process. Sphingolipids are now emerging as important regulators in various pathophysiological processes, including the atherogenic process. Various sphingolipids exist, such as the ceramides, ceramide-1-phosphate, sphingosine, sphinganine, sphingosine-1-phosphate (S1P), sphingomyelin, and hundreds of glycosphingolipids. Among these, ceramides, glycosphingolipids, and S1P play important roles in the atherogenic processes. The atherosclerotic plaque consists of higher amounts of ceramide, glycosphingolipids, and sphingomyelin. The inhibition of the de novo ceramide biosynthesis reduces the development of atherosclerosis. S1P regulates atherogenesis via binding to the S1P receptor (S1PR). Among the five S1PRs (S1PR1-5), S1PR1 and S1PR3 mainly exert anti-atherosclerotic properties. This review mainly focuses on the effects of ceramide and S1P via the S1PR in the development of atherosclerosis. Moreover, it discusses the recent findings and potential therapeutic implications in atherosclerosis.

Plasma Ceramide Levels Are Elevated in Patients With Early Coronary Atherosclerosis and Endothelial Dysfunction

“… 14 , 29 Scientists postulate that specific acyl species may be more associated with varying atherogenic pathways in humans–that is, ceramide is 18:0 associated with the inflammatory pathway, ceramide 16:0 is associated with the thrombotic pathway, and ceramide 24:1 is associated with the LDL pathway of atherogenesis. 11 , 17 , 29 , 30 In support of these associations, we present data that further suggest an association between elevated circulating ceramide 18:0 and ceramide 16:0 in humans with observed endothelial dysfunction related to early atherosclerosis. Furthermore, a linear association shows a positive association between hs‐CRP and circulating ceramide 18:0, which may be in part attributed to its role in the inflammatory pathway of atherosclerosis.…”

“… 19 Additional studies have supported that elevated levels of ceramide 24:0 may be associated with a lower risk of cardiovascular event in patients with preexisting coronary artery disease. 22 , 30 , 33 Our study interestingly finds a positive association between ceramide 24:0 in participants with early coronary atherosclerosis. Discrepancies in specific associations may be in part secondary to population selection (ie, healthy participants with stable coronary disease, participants with heart failure, population studies).…”

The sphingosine 1-phosphate receptor 2/4 antagonist JTE-013 elicits off-target effects on sphingolipid metabolism

“…As ceramide accumulation is an important event for chemotherapy efficacy and that SK1 inhibitors synergise with chemotherapy 13 , 32 , it is possible that JTE-013 may broadly synergise with anti-neoplastic drugs, as we have previously shown with venetoclax in AML cells 13 . In addition, a broad targeting agent such as JTE-013 that hits multiple arms of the sphingolipid pathway may prove favorable for therapeutic use in a range of other diseases, where sphingolipid metabolism appears important 33 – 38 . Such a paradigm already has precedent with the clinical development of FTY720 and ABC294640, which are known to have multiple targets in the sphingolipid pathway 25 , 39 .…”

Circulating Biomarkers for Laboratory Diagnostics of Atherosclerosis—Literature Review

“…In circulation, ceramides are found incorporated in the plasma lipoprotein particles [ 45 ] (their concentration being higher in LDL compared with HDL or VLDL), and have been shown to accumulate in atherosclerotic plaques [ 40 , 46 ]. Ceramides are involved in the development and progression of the atherosclerotic process through several mechanisms.…”