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J. Biol. Chem., Vol. 280, Issue 1, 669-676, January 7, 2005

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Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo^*

Joshua J. Martindale, Jason A. Wall, Diana M. Martinez-Longoria, Prafulla Aryal¶, Howard A. Rockman¶, Yiru Guo||, Roberto Bolli||, and Christopher C. Glembotski**

From the The San Diego State University Heart Institute and The Department of Biology, San Diego State University, San Diego, California 92182, ^¶Department of Medicine and Genetics, Duke University Medical Center, Durham, North Carolina 27710, and ^||Institute of Molecular Cardiology, University of Louisville, Louisville Kentucky 40292

The mitogen-activated protein kinases (MAPK) have been the subject of many studies to identify signaling pathways that promote cell survival or death. In cultured cardiac myocytes, p38 MAPK promotes cell survival or death depending on whether it is activated by mitogen-activated protein kinase kinase 6 (MKK6) or MKK3, respectively. The objectives of the current study were to examine the effects of MKK6-mediated p38 activation in the heart in vivo. Accordingly, we generated transgenic (TG) mice that overexpress wild type MKK6 in a cardiac-restricted manner. Although p38 was about 17-fold more active in TG than non-transgenic (NTG) mouse hearts, TG mouse hearts were morphologically and functionally similar to those of NTG littermates. However, upon transient ischemia followed by reperfusion, the MKK6 TG mouse hearts exhibited significantly better functional recovery and less injury than NTG mouse hearts. Because MKK6 increases levels of the protective small heat shock protein, B-crystallin (BC), in cultured cardiac myocytes, we examined BC levels in the mouse hearts. The level of BC was 2-fold higher in MKK6 TG than NTG mouse hearts. Moreover, ischemia followed by reperfusion induced a 6.4-fold increase in BC levels in the mitochondrial fractions of TG mouse hearts but no increase in BC levels in any of the other fractions analyzed. These alterations in BC expression and localization suggest possible mechanisms of cardioprotection in MKK6 TG mouse hearts.

Received for publication, June 15, 2004 , and in revised form, September 7, 2004.

^* This work was supported in part by National Institutes of Health Grants HL-63975, NS/HL-25037, and HL-75573 (to C. C. G.), HL-46345 (to H. A. R.), and HL-55757, HL-68088, and HL-70897 (to R. B.). This work was also supported in part by the Jewish Hospital Research Foundation, Louisville, KY. 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.

These authors contributed equally to this work.

^** To whom correspondence should be addressed: SDSU Heart Institute and the Dept. of Biology, San Diego State University, San Diego, CA 92182. Tel.: 619-594-2959; Fax: 619-594-5676; E-mail: cglembotski{at}sciences.sdsu.edu.

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