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J. Biol. Chem., Vol. 278, Issue 38, 36953-36958, September 19, 2003

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Heat Shock Protein 90 as an Endogenous Protein Enhancer of Inducible Nitric-oxide Synthase^*

Masako Yoshida and Yong Xia 

From the Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210

Nitric oxide (NO) generated by inducible NO synthase (iNOS) plays crucial roles in inflammation and host defense. With an intrinsically bound calmodulin, iNOS is fully active once expressed in cells. Thus, regulation of NO production from iNOS was thought to primarily occur at the enzyme transcriptional level. Here we show that NO synthesis from iNOS can be profoundly modulated by heat shock protein 90 (hsp90) through protein-protein interaction. To study whether hsp90 affects iNOS function, recombinant murine iNOS was purified from an Escherichia coli expression system by affinity chromatography. Hsp90, at physiological concentrations (10-500 nM), dose-dependently increased iNOS activity. This was a specific effect because neither denatured hsp90 nor irrelevant bovine serum albumin affected iNOS function. Overexpression of hsp90 enhanced NO production in iNOS-transfected cells. On the contrary, hsp90 inhibition dramatically decreased NO formation from iNOS in macrophages. Co-immunoprecipitation studies showed that hsp90 and iNOS associated with each other in cells. Overexpression of iNOS resulted in NO-mediated cellular injury. Hsp90 inhibition markedly attenuated NO formation and prevented cellular injury. These results demonstrated that hsp90 is an allosteric enhancer of iNOS. iNOS is coupled with hsp90 in cells, and this coupling facilitates NO synthesis. In light of the critical role of hsp90 in iNOS-mediated cytotoxic action, modulating the interaction between hsp90 and iNOS may be a new approach to intervene inflammation and immune response.

Received for publication, May 19, 2003 , and in revised form, June 25, 2003.

^* This work was supported by National Institutes of Health Grant AG00835 and a national grant-in-aid award (to Y. X.) from the American Heart Association. 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.

To whom correspondence should be addressed: The Ohio State University, 605 Davis Heart and Lung Research Institute, 473 West 12^th Ave., Columbus, OH 43210. Tel.: 614-292-5709; Fax: 614-292-6898; E-mail: xia-3{at}medctr.osu.edu.

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