Sphingosine Kinase–Dependent Activation of Endothelial Nitric Oxide Synthase by Angiotensin II
OBJECTIVE—In addition to their role in programmed cell death, cell survival, and cell growth, sphingolipid metabolites such as ceramide, sphingosine, and sphingosine-1-phosphate have vasoactive properties. Besides their occurrence in blood, they can also be formed locally in the vascular wall itself...
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Veröffentlicht in: | Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2006-09, Vol.26 (9), p.2043-2048 |
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Sprache: | eng |
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Zusammenfassung: | OBJECTIVE—In addition to their role in programmed cell death, cell survival, and cell growth, sphingolipid metabolites such as ceramide, sphingosine, and sphingosine-1-phosphate have vasoactive properties. Besides their occurrence in blood, they can also be formed locally in the vascular wall itself in response to external stimuli. This study was performed to investigate whether vasoactive compounds modulate sphingolipid metabolism in the vascular wall and how this might contribute to the vascular responses.
METHODS AND RESULTS—In isolated rat carotid arteries, the contractile responses to angiotensin II are enhanced by the sphingosine kinase inhibitor dimethylsphingosine. Endothelium removal or NO synthase inhibition by N-nitro-l-arginine results in a similar enhancement. Angiotensin II concentration-dependently induces NO production in an endothelial cell line, which can be diminished by dimethylsphingosine. Using immunoblotting and intracellular calcium measurements, we demonstrate that this sphingosine kinase–dependent endothelial NO synthase activation is mediated via both phosphatidylinositol 3-kinase/Akt and calcium-dependent pathways.
CONCLUSIONS—Angiotensin II induces a sphingosine kinase–dependent activation of endothelial NO synthase, which partially counteracts the contractile responses in isolated artery preparations. This pathway may be of importance under pathological circumstances with reduced NO bioavailability. Moreover, a disturbed sphingolipid metabolism in the vascular wall may lead to reduced NO bioavailability and endothelial dysfunction. |
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ISSN: | 1079-5642 1524-4636 |
DOI: | 10.1161/01.ATV.0000237569.95046.b9 |