on June 3, 2004
Published online before print June 3, 2004, doi: 10.1161/01.ATV.0000134300.87476.d1
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Submitted on March 10, 2004
Accepted on May 6, 2004
Heat Shock Protein 90 Transfection Reduces Ischemia-Reperfusion-Induced Myocardial Dysfunction via Reciprocal Endothelial NO Synthase Serine 1177 Phosphorylation and Threonine 495 Dephosphorylation
Christian Kupatt ;
From the Department of Medicine I (C.K., R.H., P.R., P.B.), Klinikum Großhadern, Ludwig-Maximilians-University of Munich, Germany, and Unit of Pharmacology and Therapeutics (C.D., G.D., C.B., O.F.), Department of Internal Medicine, University of Louvain Medical School, Brussels, Belgium.
* To whom correspondence should be addressed. E-mail: feron{at}mint.ucl.ac.be.
Objectives--The interaction of the heat shock protein 90 (Hsp90) with the endothelial NO synthase (eNOS) has been shown to account for a sustained production of NO in vitro. Here, we examined whether overexpression of Hsp90 in a pig model of cardiac infarct could preserve the myocardium from the deleterious effects of ischemia-reperfusion.
Methods and Results--Percutaneous liposome-based gene transfer was performed by retroinfusion of the anterior interventricular vein before left anterior descending occlusion and reperfusion. We found that recombinant Hsp90 expression in the ischemic region of the heart led to a 33% reduction in infarct size and prevented the increase in postischemic left ventricular end diastolic pressure observed in mock-transfected animals. Regional myocardial function, assessed by subendocardial segment shortening in the infarct region, was increased in Hsp90-transfected animals at baseline and after pacing. All these effects were completely abrogated by administration of the NOS inhibitor NG-nitro-L-arginine methyl ester. We further documented in vivo and in cultured endothelial cells that the cardioprotective effects of Hsp90 were associated to its capacity to act as an adaptor for both the kinase Akt and the phosphatase calcineurin, thereby promoting eNOS serine 1177 phosphorylation and threonine 495 dephosphorylation, respectively.
Conclusions--Hsp90 is a promising target to enhance NO formation in vivo, which may efficiently reduce myocardial reperfusion injury.
Key words: Hsp90 • nitric oxide • eNOS • calcineurin • Akt
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