Sphingomyelin metabolism and endothelial cell function

Serum activity of the enzyme secretory sphingomyelinase (sSM) is higher in patients with congestive heart failure (CHF) than in those with arterial hypertension or in healthy controls; more importantly, this elevation is not related to the aetiology of CHF, but rather to its severity, and well correlated with peak oxygen uptake, cytokine activation, skeletal muscle strength, and peripheral vasodilator capacity.1 In a proportional hazard analysis, serum sSM activity was related to survival independent of age, NYHA class, or blood pressure. As sSM is largely derived from the endothelium, these findings highlight the emerging role of endogenous sphingolipids as regulators of cardiovascular function and the role of the endothelium in such regulation. Against this background, we will highlight some recent findings on the complex interplay between the local formation of sphingomyelin metabolites and the endothelium. Various stressful stimuli can activate different isoforms of sphingomyelinase, which catalyses the hydrolysis of sphingomyelin to ceramide. Ceramidase can metabolize ceramide further into sphingosine, which in turn can be phosphorylated by sphingosine kinase (SphK) to yield sphingosine-1-phosphate (S1P). Other enzymes allow for a reversal of such reactions and/or can form other biologically active sphingomyelin metabolites such as sphingosylphosphorylcholine. S1P is a ligand for at least five subtypes of G-protein coupled receptors, designated S1P1–5, which were originally described as endothelial differentiation genes. S1P1–3 are the major S1P receptor subtypes expressed in the cardiovascular system, in both endothelium and vascular smooth muscle cells; at least at the mRNA level, S1P1 appears to be the most abundantly expressed subtype in the endothelium.2 In many cases, ceramide and sphingosine on the one and S1P on the other hand have opposite effects on cellular function, e.g. by stimulating cell death and apoptosis vs. cell growth and differentiation, respectively. Accordingly, sphingomyelinases … *Corresponding author. Tel: +31-20-566-6762; fax: +31-20-696-5976. E-mail address : m.c.michel{at}amc.uva.nl