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Molecular and Cellular Biology, December 2004, p. 10611-10620, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10611-10620.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

p38 Mitogen-Activated Protein Kinase Plays a Critical Role in Cardiomyocyte Survival but Not in Cardiac Hypertrophic Growth in Response to Pressure Overload

Kazuhiko Nishida,^1,2, Osamu Yamaguchi,^1, Shinichi Hirotani,¹ Shungo Hikoso,¹ Yoshiharu Higuchi,¹ Tetsuya Watanabe,¹ Toshihiro Takeda,¹ Soh Osuka,³ Takashi Morita,¹ Gen Kondoh,⁴ Yoshihiro Uno,⁴ Kazunori Kashiwase,¹ Masayuki Taniike,¹ Atsuko Nakai,¹ Yasushi Matsumura,⁵ Jun-ichi Miyazaki,⁶ Tatsuhiko Sudo,⁷ Kenichi Hongo,⁸ Yoichiro Kusakari,⁹ Satoshi Kurihara,⁹ Kenneth R. Chien,¹⁰ Junji Takeda,⁴ Masatsugu Hori,¹ and Kinya Otsu^1*

Department of Internal Medicine and Therapeutics,¹ Department of Environment and Social Science,⁴ Department of Medical Information Science,⁵ Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine,⁶ Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Osaka,² Neuronal Circuit Mechanism Research Group, Brain Science Institute,³ Antibiotics Laboratory and Bioarchitect Group, The Institute of Physical and Chemical Research (RIKEN), Wako, Saitama,⁷ Department of Cardiology,⁸ Department of Physiology, Jikei University School of Medicine, Tokyo, Japan,⁹ Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, California,¹⁰

Received 26 April 2004/ Returned for modification 1 June 2004/ Accepted 9 September 2004

The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38 is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38 in hearts. First, we generated mice with floxed p38 alleles and crossbred them with mice expressing the Cre recombinase under the control of the -myosin heavy-chain promoter to obtain cardiac-specific p38 knockout mice. These cardiac-specific p38 knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38 plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.

K.N. and O.Y. contributed equally to this work.

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