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

研究成果: Article査読

571 被引用数 (Scopus)

抄録

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 Ca 2+ 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.

本文言語English
ページ(範囲)569-581
ページ数13
ジャーナルJournal of Clinical Investigation
113
4
DOI
出版ステータスPublished - 2004 2月
外部発表はい

ASJC Scopus subject areas

  • 医学(全般)

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