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(Circulation. 2005;111:2752-2759.)
© 2005 American Heart Association, Inc.

Heart Failure

Smad1 Protects Cardiomyocytes From Ischemia-Reperfusion Injury

Mitsuru Masaki, MD^*; Masahiro Izumi, MD, PhD^*; Yuichi Oshima, MD; Yoshikazu Nakaoka, MD, PhD; Tadashi Kuroda, MD; Ryusuke Kimura, MD; Shoko Sugiyama, MD; Kazuo Terai, MD; Masafumi Kitakaze, MD, PhD; Keiko Yamauchi-Takihara, MD, PhD; Ichiro Kawase, MD, PhD; Hisao Hirota, MD, PhD

From the Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita City (M.M., Y.O., Y.N., T.K., R.K., S.S., K.T., K.Y.-T., I.K., H.H.); Department of Cardiology, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka City (M.I.); and Cardiovascular Division of Medicine, National Cardiovascular Center, Suita City (M.K.), Osaka, Japan.

Correspondence to Hisao Hirota, MD, PhD, Assistant Professor, Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita City, Osaka 565-0871, Japan. E-mail hirota{at}imed3.med.osaka-u.ac.jp

Received June 8, 2004; revision received January 25, 2005; accepted February 22, 2005.

Background— We previously reported that bone morphogenetic protein 2 (BMP2) protected against apoptosis of serum-deprived cardiomyocytes via induction of Bcl-xL through the Smad1 pathway. To investigate whether Smad1 signaling promotes cell survival in the adult heart, we subjected transgenic mice with cardiac-specific overexpression of smad1 gene (Smad1TG) to ischemia-reperfusion (I/R) injury.

Methods and Results— The effects of BMP2 or adenovirus-mediated transfection of smad1 on cardiomyocyte survival in hypoxia-reoxygenation were examined using rat neonatal cardiomyocytes. BMP2 and Smad1 each significantly promoted survival and diminished apoptotic death of cardiomyocytes during hypoxia-reoxygenation. Interestingly, Smad1 was found to be activated during I/R in normal mouse heart. To examine physiological and pathological roles of Smad1 in I/R, we generated Smad1TG using the -myosin heavy chain gene promoter. Phosphorylation of Smad1 was found in all smad1 transgene–positive mouse hearts. To examine whether Smad1 prevents injury of cardiomyocytes in vivo, we subjected Smad1TG and age-matched wild-type mice (WT) to I/R injury induced by 1 hour of ligation of the left coronary artery and 1 hour of reperfusion. TUNEL and DNA ladder analyses showed that Smad1TG had significantly smaller myocardial infarctions and fewer apoptotic deaths of cardiomyocytes than did WT. Interestingly, increased expression of Bcl-xL and ß-catenin was more remarkable whereas caspase3 was less activated in Smad1TG heart than in that of WT.

Conclusions— These findings suggest that the Smad1 signaling pathway plays a role in cardioprotection against I/R injury.

Key Words: apoptosis • hypoxia • ischemia • reperfusion • signal transduction

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