on July 20, 2006
Published online before print July 20, 2006, doi: 10.1161/01.ATV.0000237569.95046.b9
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on January 19, 2006
Accepted on June 27, 2006
Sphingosine Kinase-Dependent Activation of Endothelial Nitric Oxide Synthase by Angiotensin II
Arthur C.M. Mulders ;
From the Department of Pharmacology and Pharmacotherapy, University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands.
* To whom correspondence should be addressed. E-mail: S.L.Peters{at}amc.uva.nl.
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.
Key words: sphingosine • angiotensins • nitric oxide synthase • vasoconstriction
This article has been cited by other articles:
 |
|
 |
|
  C. K. Means and J. H. Brown Sphingosine-1-phosphate receptor signalling in the heart Cardiovasc Res, May 1, 2009; 82(2): 193 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Gossens, S. Naus, S. Y. Corbel, S. Lin, F. M.V. Rossi, J. Kast, and H. J. Ziltener Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25 J. Exp. Med., April 13, 2009; 206(4): 761 - 778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhao, S. K. Kalari, P. V. Usatyuk, I. Gorshkova, D. He, T. Watkins, D. N. Brindley, C. Sun, R. Bittman, J. G. N. Garcia, et al. Intracellular Generation of Sphingosine 1-Phosphate in Human Lung Endothelial Cells: ROLE OF LIPID PHOSPHATE PHOSPHATASE-1 AND SPHINGOSINE KINASE 1 J. Biol. Chem., May 11, 2007; 282(19): 14165 - 14177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C.M. Mulders, S. L.M. Peters, and M. C. Michel Sphingomyelin metabolism and endothelial cell function Eur. Heart J., April 1, 2007; 28(7): 777 - 779. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Suzuki, K. Eguchi, H. Ohtsu, S. Higuchi, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi Activation of Endothelial Nitric Oxide Synthase by the Angiotensin II Type 1 Receptor Endocrinology, December 1, 2006; 147(12): 5914 - 5920. [Abstract] [Full Text] [PDF]
|
|