Published Online
on May 23, 2005

A more recent version of this article appeared on May 31, 2005

This Article Full Text (PDF) Data Supplement All Versions of this Article: 111/21/2752    most recent CIRCULATIONAHA.104.490946v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Masaki, M. Articles by Hirota, H. Search for Related Content PubMed PubMed Citation Articles by Masaki, M. Articles by Hirota, H. Related Collections Apoptosis Physiological and pathological control of gene expression

Submitted on June 8, 2004
Revised on January 25, 2005
Accepted on February 22, 2005

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, and 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.

^* To whom correspondence should be addressed. E-mail: hirota{at}imed3.med.osaka-u.ac.jp.

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 -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

This article has been cited by other articles:

				Y. Oshima, N. Ouchi, M. Shimano, D. R. Pimentel, K. N. Papanicolaou, K. D. Panse, K. Tsuchida, E. Lara-Pezzi, S.-J. Lee, and K. Walsh Activin A and Follistatin-Like 3 Determine the Susceptibility of Heart to Ischemic Injury Circulation, October 20, 2009; 120(16): 1606 - 1615. [Abstract] [Full Text] [PDF]

				M. Korf-Klingebiel, T. Kempf, T. Sauer, E. Brinkmann, P. Fischer, G. P. Meyer, A. Ganser, H. Drexler, and K. C. Wollert Bone marrow cells are a rich source of growth factors and cytokines: implications for cell therapy trials after myocardial infarction Eur. Heart J., December 1, 2008; 29(23): 2851 - 2858. [Abstract] [Full Text] [PDF]

				Y.-X. Wang, L.-X. Qian, D. Liu, L.-L. Yao, Q. Jiang, Z. Yu, Y.-H. Gui, T. P. Zhong, and H.-Y. Song Bone morphogenetic protein-2 acts upstream of myocyte-specific enhancer factor 2a to control embryonic cardiac contractility Cardiovasc Res, May 1, 2007; 74(2): 290 - 303. [Abstract] [Full Text] [PDF]

				T. Ago and J. Sadoshima GDF15, a Cardioprotective TGF-{beta} Superfamily Protein Circ. Res., February 17, 2006; 98(3): 294 - 297. [Full Text] [PDF]

				K. Terai, Y. Hiramoto, M. Masaki, S. Sugiyama, T. Kuroda, M. Hori, I. Kawase, and H. Hirota AMP-Activated Protein Kinase Protects Cardiomyocytes against Hypoxic Injury through Attenuation of Endoplasmic Reticulum Stress Mol. Cell. Biol., November 1, 2005; 25(21): 9554 - 9575. [Abstract] [Full Text] [PDF]