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(Circulation. 2006;113:1787-1798.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Role of p90 Ribosomal S6 Kinase–Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium

Seigo Itoh, MD, PhD; Bo Ding, MD; Tetsuro Shishido, MD, PhD; Nicole Lerner-Marmarosh, PhD; Nadan Wang, MS; Naoya Maekawa, PhD; Bradford C. Berk, MD, PhD; Yasuchika Takeishi, MD, PhD; Chen Yan, PhD; Burns C. Blaxall, PhD; Jun-ichi Abe, MD, PhD

From the Cardiovascular Research Institute (S.I., B.D., T.S., N.L.-M., N.W., N.M., B.C. Berk, C.Y., B.C. Blaxall, J.-i.A.), University of Rochester, Rochester, NY; and Department of Internal Medicine, Yamagata University (Y.T.), Yamagata, Japan.

Correspondence to Jun-ichi Abe, MD, PhD, Cardiovascular Research Institute, 601 Elmwood Ave, Box 679, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642. E-mail jun-ichi_abe{at}urmc.rochester.edu

Received July 25, 2005; revision received February 7, 2006; accepted February 9, 2006.

Background— Epidemiological data strongly indicate that diabetes increases the incidence of heart failure. Although the benefit of angiotensin-converting enzyme inhibitor (ACE-I) treatment during and after myocardial infarction has been found to be greater in diabetics than nondiabetics and activation of the renin-angiotensin system (RAS) has been implicated, the molecular basis of these actions remains unclear.

Methods and Results— We generated transgenic mice with cardiac-specific overexpression of wild-type p90 ribosomal S6 kinase (WT-p90RSK-Tg) and a dominant-negative form of p90RSK (DN-p90RSK-Tg). Recovery of cardiac function after ischemia/reperfusion in WT-p90RSK-Tg isolated mouse hearts was significantly impaired. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry revealed specific induction of prorenin-converting enzyme (PRECE) in WT-p90RSK-Tg mice. mRNA induction of PRECE was confirmed with serial angiotensinogen protein reduction after perfusion in WT-p90RSK-Tg mice, suggesting an increase of angiotensinogen cleavage and subsequent RAS activation in WT-p90RSK-Tg mice. We investigated the role of the RAS in WT-p90RSK-Tg animals after ischemia/reperfusion with the use of an ACE-I (captopril) and an angiotensin II type 1 receptor blocker (olmesartan). We did not observe any effect of these inhibitors in non-Tg littermate controls, thus corroborating other reports in rodents. In contrast, both captopril and olmesartan significantly improved cardiac function and reduced infarct size in WT-p90RSK-Tg mice. At 8 months of age, WT-p90RSK-Tg mice developed cardiac dysfunction. p90RSK activity and PRECE mRNA were both increased by streptozotocin-induced hyperglycemia in non-Tg littermate controls, whereas DN-p90RSK-Tg animals exposed to streptozotocin did not have PRECE induction.

Conclusions— This study demonstrates the critical role of p90RSK in hyperglycemia-mediated myocardial PRECE induction, which may explain the augmentation of the RAS in diabetic hearts and provide an alternative therapeutic approach to treat diabetic cardiomyopathy.

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