HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: db06-1418v1 56/5/1445    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by You, B. Articles by Sun, J. Search for Related Content PubMed PubMed Citation Articles by You, B. Articles by Sun, J. Social Bookmarking                What's this?

Activation of Sphingosine kinase-1 Mediates Inhibition of Vascular Smooth Muscle Cell Apoptosis by Hyperglycemia

¹Department of Cell Biology and Molecular Medicine, UMDNJ-New Jersey Medical School, Newark, NJ

Correspondence: sunj1{at}umdnj.edu

Vascular smooth muscle cell (VSMC) apoptosis plays an essential role in vascular development and atherosclerosis. Hyperglycemia inhibits VSMC apoptosis, which may contribute to the development of diabetic vasculopathy. In the present study, we analyzed the mechanism of high glucose induced anti-apoptotic effect in cultured human aortic smooth muscle cells (HASMCs). Compared with normoglycemia, exposure of HASMCs to hyperglycemia, but not mannitol, significantly increased SK1 activity, but not SK2 activity. This increase was inhibited by a PKC inhibitor, GF109203X, the antioxidant N-acetylcysteine (NAC), and the reduced form of glutathione (GSH). The mechanism of SK1 activation by high glucose involves plasma membrane translocation. In addition, hyperglycemia markedly inhibited serum withdrawal induced apoptosis in HASMCs. Importantly, inhibition of SK1 by either a competitive inhibitor N',N'-dimethylsphingosine (DMS) or expression of dominant negative mutant of SK1(G82D), or specific siRNA knockdown, substantially attenuated hyperglycemia induced anti-apoptotic effect and anti-apoptotic protein Bcl-2 expression in HASMCs. Moreover, SK1 mediated anti-apoptotic effect requires the intracellular effects of S1P. We conclude that hyperglycemia stimulates SK1 activity via PKC and oxidative stress-dependent pathways, leading to decreased apoptosis in HASMCs. Taken together, these observations have important implications for understanding the roles of the SK1 signaling pathway in the pathogenesis of diabetic vasculopathy.

CiteULike

Del.icio.us

Digg

Reddit

Technorati