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

Research output: Contribution to journalArticle

506 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)569-581
Number of pages13
JournalJournal of Clinical Investigation
Volume113
Issue number4
DOIs
Publication statusPublished - 2004 Feb
Externally publishedYes

Fingerprint

Lysophospholipid Receptors
Lysophospholipids
Vasodilation
Arterial Pressure
Endothelial Cells
Phosphorylation
Scavenger Receptors
Blood Vessels
Aorta

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Nofer, J. R., Van Der Giet, M., Tölle, M., Wolinska, I., Von Wnuck Lipinski, K., Baba, H. A., ... Levkau, B. (2004). HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3 Journal of Clinical Investigation, 113(4), 569-581. https://doi.org/10.1172/JCI200418004

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

In: Journal of Clinical Investigation, Vol. 113, No. 4, 02.2004, p. 569-581.

Research output: Contribution to journalArticle

Nofer, JR, Van Der Giet, M, Tölle, M, Wolinska, I, Von Wnuck Lipinski, K, Baba, HA, Tietge, UJ, Gödecke, A, Ishii, I, Kleuser, B, Schäfers, M, Fobker, M, Zidek, W, Assmann, G, Chun, J & Levkau, B 2004, 'HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3 ', Journal of Clinical Investigation, vol. 113, no. 4, pp. 569-581. https://doi.org/10.1172/JCI200418004
Nofer JR, Van Der Giet M, Tölle M, Wolinska I, Von Wnuck Lipinski K, Baba HA et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3 Journal of Clinical Investigation. 2004 Feb;113(4):569-581. https://doi.org/10.1172/JCI200418004
Nofer, Jerzy Roch ; Van Der Giet, Markus ; Tölle, Markus ; Wolinska, Iza ; Von Wnuck Lipinski, Karin ; Baba, Hideo A. ; Tietge, Uwe J. ; Gödecke, Axel ; Ishii, Isao ; Kleuser, Burkhard ; Schäfers, Michael ; Fobker, Manfred ; Zidek, Walter ; Assmann, Gerd ; Chun, Jerold ; Levkau, Bodo. / HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3 In: Journal of Clinical Investigation. 2004 ; Vol. 113, No. 4. pp. 569-581.
@article{ce6c4afbf10949558ce749a42174e128,
title = "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 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.",
author = "Nofer, {Jerzy Roch} and {Van Der Giet}, Markus and Markus T{\"o}lle and Iza Wolinska and {Von Wnuck Lipinski}, Karin and Baba, {Hideo A.} and Tietge, {Uwe J.} and Axel G{\"o}decke and Isao Ishii and Burkhard Kleuser and Michael Sch{\"a}fers and Manfred Fobker and Walter Zidek and Gerd Assmann and Jerold Chun and Bodo Levkau",
year = "2004",
month = "2",
doi = "10.1172/JCI200418004",
language = "English",
volume = "113",
pages = "569--581",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

TY - JOUR

T1 - HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3

AU - Nofer, Jerzy Roch

AU - Van Der Giet, Markus

AU - Tölle, Markus

AU - Wolinska, Iza

AU - Von Wnuck Lipinski, Karin

AU - Baba, Hideo A.

AU - Tietge, Uwe J.

AU - Gödecke, Axel

AU - Ishii, Isao

AU - Kleuser, Burkhard

AU - Schäfers, Michael

AU - Fobker, Manfred

AU - Zidek, Walter

AU - Assmann, Gerd

AU - Chun, Jerold

AU - Levkau, Bodo

PY - 2004/2

Y1 - 2004/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=11144356028&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=11144356028&partnerID=8YFLogxK

U2 - 10.1172/JCI200418004

DO - 10.1172/JCI200418004

M3 - Article

VL - 113

SP - 569

EP - 581

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -