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J. Biol. Chem., Vol. 283, Issue 15, 9595-9605, April 11, 2008

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Oxysterol and Diabetes Activate STAT3 and Control Endothelial Expression of Profilin-1 via OSBP1^*

From the Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114

Endothelial dysfunction plays a central role in diabetic vascular disease, but its molecular bases are not completely defined. We showed previously that the actin-binding protein proflin-1 was increased in the diabetic endothelium and that attenuated expression of profilin-1 protected against atherosclerosis. Also 7-ketocholesterol up-regulated profilin-1 in endothelial cells via transcriptional mechanisms. The present study addressed the pathways responsible for profilin-1 gene expression in 7-ketocholesterol-stimulated endothelial cells and in the diabetic aorta. In luciferase reporter assays, the response to 7-ketocholesterol within the 5'-flanking region of profilin-1 was dependent on a single STAT response element. In aortic endothelial cells, 7-ketocholesterol enhanced STAT3 activation, which required JAK2 and tyrosine 394 phosphorylation of oxysterol-binding protein-1. These changes were recapitulated in the aorta of diabetic rats. Also 7-ketocholesterol in cultured endothelial cells and diabetes in the aorta elicited the recruitment of STAT3 and relevant coregulatory factors to the oxysterol-responsive region of the profilin-1 promoter. These events were required for profilin-1 up-regulation. These studies identify a previously unrecognized oxysterol-binding protein-mediated mode of activation of STAT3 that controls the expression of the proatherogenic protein profilin-1 in response to 7-ketocholesterol and the diabetic milieu.

Received for publication, December 11, 2007 , and in revised form, January 25, 2008.

^* This work was supported by Juvenile Diabetes Research Foundation Career Development Award 2-2004-609 (to G. R. R.) and the "U. Di Mario" Fellowship from FO.Ri.SID (to G. R. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Joslin Diabetes Center, One Joslin Place, Boston, MA 02115. Tel.: 617-732-2669; Fax: 617-732-2407; E-mail: giulio.romeo{at}joslin.harvard.edu.

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