The antithetic role of ceramide and sphingosine‐1‐phosphate in cardiac dysfunction

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death globally and the number of cardiovascular patients, which is estimated to be over 30 million in 2018, represent a challenging issue for the healthcare systems worldwide. Therefore, the identification of novel molecular targets to develop new treatments is an ongoing challenge for the scientific community. In this context, sphingolipids (SLs) have been progressively recognized as potent bioactive compounds that play crucial roles in the modulation of several key biological processes, such as proliferation, differentiation, and apoptosis. Furthermore, SLs involvement in cardiac physiology and pathophysiology attracted much attention, since these molecules could be crucial in the development of CVDs. Among SLs, ceramide and sphingosine‐1‐phosphate (S1P) represent the most studied bioactive lipid mediators, which are characterized by opposing activities in the regulation of the fate of cardiac cells. In particular, maintaining the balance of the so‐called ceramide/S1P rheostat emerged as an important novel therapeutical target to counteract CVDs. Thus, this review aims at critically summarizing the current knowledge about the antithetic roles of ceramide and S1P in cardiomyocytes dysfunctions, highlighting how the modulation of their metabolism through specific molecules, such as myriocin and FTY720, could represent a novel and interesting therapeutic approach to improve the management of CVDs.

The Complex Tail of Circulating Sphingolipids in Atherosclerosis and Cardiovascular Disease

“…Furthermore, administration of myriocin, a SL synthesis inhibitor that reduces ceramide and SM levels, decreased the propensity of LDL to aggregate and ameliorated atherosclerotic plaque formation in mice. 90 98 99 100 Whether such an approach is feasible in humans 101 remains to be tested.…”

Huoxue Qingre decoction used for treatment of coronary heart disease network analysis and metabolomic evaluation

“…SM is mainly located on the cell membrane, lipoproteins (especially LDL), and other lipid-rich tissue structures, which is very important for maintaining the micro-control function of the cell membrane structure so that it can regulate the activity of growth factor receptors and extracellular matrix proteins. Its degradation and anabolic intermediates are known as sphingomyelins, which have the effect of regulating cell biological functions ( Cirillo et al, 2021 ). The metabolites of SM include ceramide (Cer) and sphingosine-1-phosphate (S1P), of which Cer is a central molecule in sphingomyelin metabolism, and its biological functions mainly include inducing apoptosis, and the regulation of cell differentiation, cellular immunity, and inflammatory responses.…”

“…In this process, sphingomyelinase (SMase) is the key enzyme regulating SM metabolism, which can decompose SM to produce Cer and phosphorylcholine. Cer is cleaved to sphingosine (Sph) by ceramidase (CDase), and phosphatidylcholine generates S1P by sphingosine kinase (SphK), which then activates the downstream MAPK, BAX/BCL-2, and PI3K/AKT signaling pathways involved in the regulation of cell proliferation and apoptosis ( Nishino et al, 2019 ; Cirillo et al, 2021 ; Green et al, 2021 ). The current study showed that higher plasma levels of Cer-16 and SM-16 were associated with increased risk of heart failure, and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure ( Lemaitre et al, 2019 ; Fretts et al, 2021 ).…”

Age-Related Alterations in the Testicular Proteome of a Non-Human Primate

“…It may also influence steroidogenesis directly by binding to NR5A1 [ 59 , 60 ]. Its substrate, ceramide, is a bioactive lipid which regulates apoptosis, differentiation but also proliferation [ 61 , 62 ]. In human ovarian granulosa cells, it induced cell death [ 63 ].…”