Sphingomyelinases: their regulation and roles in cardiovascular pathophysiology

Abstract

Sphingomyelinases (SMases) hydrolyse sphingomyelin, releasing ceramide and creating a cascade of bioactive lipids. These lipids include sphingosine and sphingosine-1-phosphate, all of which have a specific signalling capacity. Sphingomyelinase activation occurs in different cardiovascular system cell types, namely cardiac myocytes, endothelial and vascular smooth muscle cells, mediating cell proliferation, cell death, and contraction of cardiac and vascular myocytes. Three main types of SMases contribute to cardiovascular physiology: the lysosomal and secreted acidic SMases (L- and S-ASMases, respectively) and the membrane neutral SMase (NSMase). These three enzymes have common activators, including ischaemia/reperfusion stress and proinflammatory cytokines, but they differ in their enzymatic properties and subcellular locations that determine the final effect of enzyme activation. This review focuses on the recent advances in the understanding of ASMase and NSMase pathways and their specific contribution to cardiovascular pathophysiology. Current knowledge indicates that the inhibitors of the different SMase types are potential tools for the treatment of cardiovascular diseases. Acid SMase inhibitors could be tools against post-ischaemia reperfusion injury and in the treatment of atherosclerosis. Neutral SMase inhibitors could be tools for the treatment of atherosclerosis, heart failure, and age-related decline in vasomotion. However, the design of bioavailable and more specific SMase-type inhibitors remains a challenge.

Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation

“…Since then nSMase2 has been established as a key regulator of exosome secretion and cell-stress responses and has been implicated in cancer (32,33), Alzheimer's disease (34,35), and cardiovascular disease (53). Based on our biochemical and structural experiments, we now are able to propose a model for the activation of nSMase2.…”

Secretory sphingomyelinase in health and disease

“…However, in mammalian organisms the role, function and regulation of S-ASM are not as well understood as those of L-ASM. Several previous reviews cover various aspects of S-ASM physiology and pathophysiology (Tabas, 1999;Goni and Alonso, 2002;Smith and Schuchman, 2008;Jenkins et al, 2009;Pavoine and Pecker, 2009;He and Schuchman, 2012). In this review, we focus on the progress made in recent years specifically on mammalian S-ASM and some aspects of secreted L-ASM, and we examine novel studies investigating S-ASM as a mediator of pathogenic processes, a potential therapeutic target and a biomarker in human diseases.…”

New Insights into the Regulation of Serine Palmitoyltransferase

“…Sphingomyelinase activity in cardiovascular cells results in release of ceramides which signals contraction of cardiac myocytes (68). It has been reported that inhibition of sphingomyelinase prevents cardiovascular diseases like atherosclerosis and thrombosis by reducing the production of ceramides (66).…”