p38α mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload

被引:195
作者
Nishida, K
Yamaguchi, O
Hirotani, S
Hikoso, S
Higuchi, Y
Watanabe, T
Takeda, T
Osuka, S
Morita, T
Kondoh, G
Uno, Y
Kashiwase, K
Taniike, M
Nakai, A
Matsumura, Y
Miyazaki, J
Sudo, T
Hongo, K
Kusakari, Y
Kurihara, S
Chien, KR
Takeda, J
Hori, M
Otsu, K
机构
[1] Osaka Univ, Grad Sch Med, Dept Internal Med & Therapeut, Suita, Osaka 5650871, Japan
[2] Osaka Univ, Grad Sch Med, Dept Environm & Social Sci, Suita, Osaka 5650871, Japan
[3] Osaka Univ, Grad Sch Med, Dept Med Informat Sci, Suita, Osaka 5650871, Japan
[4] Osaka Univ, Grad Sch Med, Div Stem Cell Regulat Res, Suita, Osaka 5650871, Japan
[5] Osaka Univ, Grad Sch Dent, Dept Dent Anesthesiol, Suita, Osaka, Japan
[6] Brain Sci Inst, Neuronal Circuit Mech Res Grp, Wako, Saitama, Japan
[7] RIKEN, Antibiot Lab, Inst Phys & Chem Res, Wako, Saitama 35101, Japan
[8] RIKEN, Bioarchitect Grp, Inst Phys & Chem Res, Wako, Saitama 35101, Japan
[9] Jikei Univ, Sch Med, Dept Cardiol, Tokyo, Japan
[10] Jikei Univ, Sch Med, Dept Physiol, Tokyo, Japan
[11] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA
关键词
D O I
10.1128/MCB.24.24.10611-10620.2004
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 p38alpha 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 p38alpha in hearts. First, we generated mice with floxed p38alpha alleles and crossbred them with mice expressing the Cre recombinase under the control of the alpha-myosin heavy-chain promoter to obtain cardiac-specific p38alpha knockout mice. These cardiac-specific p38alpha 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 p38alpha 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.
引用
收藏
页码:10611 / 10620
页数:10
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