HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3

Abstract

HDL is a major atheroprotective factor, but the mechanisms underlying this effect are still obscure. HDL binding to scavenger receptor-BI has been shown to activate eNOS, although the responsible HDL entities and signaling pathways have remained enigmatic. Here we show that HDL stimulates NO release in human endothelial cells and induces vasodilation in isolated aortae via intracellular Ca2+ mobilization and Akt-mediated eNOS phosphorylation. The vasoactive effects of HDL could be mimicked by three lysophospholipids present in HDL: sphingosylphosphorylcholine (SPC), sphingosine-1-phosphate (S1P), and lysosulfatide (LSF). All three elevated intracellular Ca2+ concentration and activated Akt and eNOS, which resulted in NO release and vasodilation. Deficiency of the lysophospholipid receptor S1P3 (also known as LPB3 and EDG3) abolished the vasodilatory effects of SPC, S1P, and LSF and reduced the effect of HDL by approximately 60%. In endothelial cells from S1P3-deficient mice, Akt phosphorylation and Ca2+ increase in response to HDL and lysophospholipids were severely reduced. In vivo, intra-arterial administration of HDL or lysophospholipids lowered mean arterial blood pressure in rats. In conclusion, we identify HDL as a carrier of bioactive lysophospholipids that regulate vascular tone via S1P3-mediated NO release. This mechanism may contribute to the vasoactive effect of HDL and represent a novel aspect of its antiatherogenic function

Weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice

“…In addition to the role of HDL in the uptake of peripheral cholesterol, HDL also exerts direct vasoprotective actions. HDL restores endothelium-dependent vasodilatation (Spieker et al 2002;Bisoendial et al 2003), stimulates endothelial nitric oxide (Yuhanna et al 2001;Nofer et al 2004), exerts antioxidant actions (Nicholls et al 2005), promotes endothelial cell repair (Tso et al 2006;Sumi et al 2007), and downregulates angiotensin II type 1 receptors (Van Linthout et al 2009). Currently, HDL-raising therapies are under intense evaluation (Lee et al 2009;Hamilton et al 2010;Sorrentino et al 2010).…”

HDL and its sphingosine-1-phosphate content in cardioprotection

“…However, little is known about the exact nature of these mechanisms or the molecular entities inside the large and complex HDL particle that mediate them. Recently, the author and others have identified the bioactive lipid sphingosine-1-phosphate (S1P) as an intrinsic component of human HDL and have characterized it as partially responsible for several of the physiological HDL functions apart from reverse cholesterol transport [13,14]. This review focuses on the in vitro and in vivo evidence that allows us to attribute the beneficial effect of HDL in myocardial ischemia/reperfusion injury as well as preconditioning to its S1P content.…”

HDL-Bound Sphingosine 1-Phosphate (S1P) Predicts the Severity of Coronary Artery Atherosclerosis

“…As HDL are complex particles composed of dozens of proteins and hundreds of different lipids, much attention has been given to the molecular entities inside HDL that mediate individual biological effects. We and others have identified the biologically active sphingolipid sphingosine 1-phosphate (S1P) that is contained in HDL to be responsible for several of their potentially vaso- and cardioprotective functions [6,7,8,9,10,11]. Recently, we have demonstrated that the plasma S1P levels are elevated and that its distribution shifted from HDL towards non-HDL-carriers in stable CAD and acute myocardial infarction [12].…”