Targeted disruption of Smad4 in cardiomyocytes results in cardiac hypertrophy and heart failure.
Transforming growth factor-betas (TGF-betas) are pleiotropic cytokines involved in many physiological and pathological processes, including heart development and heart disease. Smad4 is the central intracellular mediator of TGF-beta 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-beta could be a mechanism by which cardiac myocytes undergo hypertrophy.
Wang
Jian
J
Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, People's Republic of China.
Xu
Ning
N
Feng
Xinheng
X
Hou
Ning
N
Zhang
JiShuai
J
Cheng
Xuan
X
Chen
Yeguang
Y
Zhang
Youyi
Y
Yang
Xiao
X
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology*; D048429:Cell Size; D004789:Enzyme Activation; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000473:pathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1
C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases