HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3
Jerzy-Roch Nofer, … , Jerold Chun, Bodo Levkau
Jerzy-Roch Nofer, … , Jerold Chun, Bodo Levkau
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):569-581. https://doi.org/10.1172/JCI18004.
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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-associated lysophospholipids induce vasorelaxation in isolated arter...
HDL-associated lysophospholipids induce vasorelaxation in isolated arteries and NO production and eNOS phosphorylation in endothelial cells. (a) Following precontraction of thoracic aortic rings from WKY rats with PE (1 0 10–6 mol/l), measurements were taken of direct relaxation responses to HDL (0.5 mg/ml), the HDL-lipid fraction (Lipid, equivalent to 0.5 mg/ml HDL), the HDL protein fraction (Protein, equivalent to 0.5 mg/ml HDL), apoAI (0.1 mg/ml), cholesterol (Chol, 10 μmol/l), phosphatidylcholine (PC, 10 μmol/l), and sphingomyelin (Sm, 10 μmol/l). Cumulative findings (mean ± SEM) for maximal relaxation in eight experiments are shown (*P < 0.01 vs. HDL). (b) HPLC profile of S1P and dihydro-S1P separated on a reverse-phase C18 column after a two-step lipid extraction and derivatization with o-phthaldialdehyde (upper left panel) is shown beside a representative HPLC chromatogram of HDL after addition of dihdro-S1P (50 pmol) before extraction procedures (upper right panel). HPLC chromatogram of o-phthaldialdehyde derivatives of SPC: 0.5 μmol SPC standard (lower left panel) and HDL (lower right panel). arb U, arbitrary units. (c) Following precontraction of thoracic aortic rings from WT 129/C57BL/6 mice (WT) or eNOS–/– mice with PE (1 × 10–6 mol/l), direct relaxation responses to HDL (0.5 mg/ml), SPC (10 μmol/l), LSF (10 μmol/l), and S1P (10 μmol/l) were tested. Cumulative findings (mean ± SEM) for maximal relaxation in eight experiments are shown (*P < 0.01 vs. WT). (d) Following precontraction of thoracic aortic rings from WKY rats with PE, direct relaxation responses to different doses of SPC, S1P, and LSF were measured. Cumulative findings (mean ± SEM) for maximal relaxation in eight experiments are shown.