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(Circulation Research. 2005;97:821.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Targeted Disruption of Smad4 in Cardiomyocytes Results in Cardiac Hypertrophy and Heart Failure

Jian Wang^*, Ning Xu^*, Xinheng Feng, Ning Hou, JiShuai Zhang, Xuan Cheng, Yeguang Chen, Youyi Zhang, Xiao Yang

From the Genetic Laboratory of Development and Diseases (J.W., N.H., J.Z., X.C., X.Y.), Institute of Biotechnology, Beijing; Institute of Vascular Medicine (N.X., X.F., Y.Z.), Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing; Department of Biological Sciences and Biotechnology (Y.C.), Tsinghua University, Beijing, People’s Republic of China

Correspondence to Xiao Yang, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, People’s Republic of China. E-mail yangx{at}nic.bmi.ac.cn; or Youyi Zhang, Institute of Vascular Medicine, Peking University Third Hospital, 49 Huayuan-Bei Rd, Beijing 100085, People’s Republic of China. E-mail zhangyy@bjmu.edu.cn

Transforming growth factor-ßs (TGF-ßs) are pleiotropic cytokines involved in many physiological and pathological processes, including heart development and heart disease. Smad4 is the central intracellular mediator of TGF-ß signaling. To investigate the function of Smad4 in heart development further, we generated a strain of cardiomyocyte-specific Smad4 knockout mice using the Cre–loxP system. Unexpectedly, the deletion of Smad4 in cardiomyocytes resulted in cardiac hypertrophy characterized by an increase in the size of cardiac myocytes, age-associated fibrosis, and reexpression of certain fetal genes. Approximately 70% of the Smad4 mutant mice died spontaneously between 5 and 12 months of age. Echocardiography and an invasive hemodynamic study of the left ventricle revealed markedly decreased cardiac contractility in Smad4 mutant mice compared with littermate controls. Moreover, phosphorylated extracellular signal–regulated kinase (ERK) 1/2 and mitogen-activated protein kinase–ERK (MEK) 1 were increased in the Smad4 mutants, suggesting that an upregulation of MEK1–ERK1/2 signaling as a consequence of deletion of Smad4 underlies the impaired cardiac function. These results reveal an important function of Smad4 in cardiac remodeling and suggest that an altered cellular response to TGF-ß could be a mechanism by which cardiac myocytes undergo hypertrophy.

Key Words: Smad4 • cardiac hypertrophy • heart failure • mitogen-activated protein kinase • Cre–LoxP system

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