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J. Biol. Chem., Vol. 282, Issue 13, 9364-9371, March 30, 2007

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Protein Kinase A-dependent Translocation of Hsp90 Impairs Endothelial Nitric-oxide Synthase Activity in High Glucose and Diabetes^*

From the Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114

Diabetes mellitus (DM) and high glucose (HG) are known to reduce the bioavailability of nitric oxide (NO) by modulating endothelial nitric-oxide synthase (eNOS) activity. eNOS is regulated by several mechanisms including its interaction with heat shock protein (Hsp) 90. We previously discovered that DM in vivo and HG in vitro induced the translocation of Hsp90 to the outside of aortic endothelial cells. In this report we tested the hypothesis that translocation of Hsp90 is responsible for the decline in NO production observed in HG-treated cells. We found that HG increased phosphorylation of Hsp90 in a cAMP-dependent protein kinase A-dependent manner, and that this event was required for translocation of Hsp90 in porcine aortic endothelial cells. Furthermore, preventing translocation of Hsp90 protected from the HG-induced decline in eNOS·Hsp90 complex and NO production. Notably, DM increased phosphorylation of Hsp90 and reduced its association with eNOS in the aortic endothelium of diabetic rats. These studies suggest that translocation of Hsp90 is a novel mechanism by which HG and DM impair eNOS activity and thereby reduce NO production.

Received for publication, September 21, 2006 , and in revised form, December 4, 2006.

^* This work was supported by Juvenile Diabetes Research Foundation Center for Diabetic Retinopathy, Schepens Eye Research Institute Grant 4-2000-650. 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. S1–S5.

¹ To whom correspondence should be addressed: 20 Staniford St., Boston, MA 02114. Tel.: 617-912-2517; Fax: 617-912-0101; E-mail: ak{at}eri.harvard.edu.

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