HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3
Jerzy-Roch Nofer, Markus van der Giet, Markus Tölle, Iza Wolinska, Karin von Wnuck Lipinski, Hideo A. Baba, Uwe J. Tietge, Axel Gödecke, Isao Ishii, Burkhard Kleuser, Michael Schäfers, Manfred Fobker, Walter Zidek, Gerd Assmann, Jerold Chun, Bodo Levkau
Jerzy-Roch Nofer, Markus van der Giet, Markus Tölle, Iza Wolinska, Karin von Wnuck Lipinski, Hideo A. Baba, Uwe J. Tietge, Axel Gödecke, Isao Ishii, Burkhard Kleuser, Michael Schäfers, Manfred Fobker, Walter Zidek, Gerd Assmann, Jerold Chun, Bodo Levkau
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Article Cardiology

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.

Authors

Jerzy-Roch Nofer, Markus van der Giet, Markus Tölle, Iza Wolinska, Karin von Wnuck Lipinski, Hideo A. Baba, Uwe J. Tietge, Axel Gödecke, Isao Ishii, Burkhard Kleuser, Michael Schäfers, Manfred Fobker, Walter Zidek, Gerd Assmann, Jerold Chun, Bodo Levkau

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HDL induces vasodilation in aortae from rats and mice in an eNOS-depende...
HDL induces vasodilation in aortae from rats and mice in an eNOS-dependent manner. (a) Thoracic aortic rings from WKY rats were precontracted with PE (1 × 106 mol/l, arrows), and direct relaxation responses to HDL (0.5 mg/ml) or HDL and L-NAME (50 μmol/l) were evaluated. Shown are representative tracings from one experiment of 16. (b) Cumulative findings (mean ± SEM) for maximal relaxation in response to 0.5 mg/ml HDL in the presence of L-NAME (50 μmol/l), SKF-525A ((SKF, 50 μmol/l), or indomethacin (Indo, 10 μmol/l) (n = 6 each). *P < 0.01 vs. HDL. (c) HUVECs loaded with DAF-2DA were stimulated with 0.5 mg/ml HDL in the absence or presence of L-NAME. Cells were fixed and fluorescence was evaluated under a fluorescence microscope. Shown are representative results (n = 5). (d) Dose response of the vasodilatory effect of HDL (n = 3). (e) Thoracic aortic rings from WT 129/C57BL/6 mice and eNOS–/– mice were precontracted with PE, and direct relaxation responses to HDL (0.5 mg/ml) were measured. Shown are representative tracings from one experiment of six.