Sphingolipids in the Heart: From Cradle to Grave

Abstract

Cardiovascular diseases are the leading cause of mortality worldwide and this has largely been driven by the increase in metabolic disease in recent decades. Metabolic disease alters metabolism, distribution, and profiles of sphingolipids in multiple organs and tissues; as such, sphingolipid metabolism and signaling have been vigorously studied as contributors to metabolic pathophysiology in various pathological outcomes of obesity, including cardiovascular disease. Much experimental evidence suggests that targeting sphingolipid metabolism may be advantageous in the context of cardiometabolic disease. The heart, however, is a structurally and functionally complex organ where bioactive sphingolipids have been shown not only to mediate pathological processes, but also to contribute to essential functions in cardiogenesis and cardiac function. Additionally, some sphingolipids are protective in the context of ischemia/reperfusion injury. In addition to mechanistic contributions, untargeted lipidomics approaches used in recent years have identified some specific circulating sphingolipids as novel biomarkers in the context of cardiovascular disease. In this review, we summarize recent literature on both deleterious and beneficial contributions of sphingolipids to cardiogenesis and myocardial function as well as recent identification of novel sphingolipid biomarkers for cardiovascular disease risk prediction and diagnosis.

Keywords: cardiovascular disease; ceramide; heart development; sphingolipids; sphingosine-1-phosphate.

Figure 1

(A) Sphingolipid de novo synthesis. Overview of sphingolipid structure and metabolism. ssSPTa, small SPT subunit a; ssSPTb, small SPT subunit b; DHS, dihydrosphingosine; CerS, ceramide synthase; DHC, dihydroceramide; DES, DHC desaturase; SM, sphingomyelin; GSL, glycosphingolipid. (B) Sphingolipids involved in cardiogenesis. The receptors S1PR1-3, Spns2, OGR1, GPR12 and the sphingolipids S1P and SPC are highly expressed in stem cells that migrate to form the primitive heart tube. Normal expression of S1P via the S1PR1 receptor is needed for normal heart looping. Ceramide and S1P via the Cert and S1PR3 receptors, respectively, are required for chamber and septal formation. Cardia bifida is observed after failure of the myocardial cells to coalesce into one single primitive heart tube. Overexpression of Spns2 or S1PR1 or mutation of S1PR2 causes cardia bifida.