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Activation of TGF-1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats

Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

Submitted 25 February 2005 ; accepted in final form 19 September 2005

Transforming growth factor-1 (TGF-1) alters myocardial gene expression, resulting in myocyte hypertrophy, through activation of TGF--activated kinase (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family. We hypothesized that the TGF-1-TAK1-p38 MAPK pathway might be activated during ventricular remodeling after myocardial infarction (MI). One, 3, 7, and 14 days after ligation of the left anterior descending coronary artery, noninfarcted left ventricular tissue samples were obtained. Protein levels as well as mRNA levels of the signaling pathway, TGF-1, TGF--receptors, and TAK1 increased in the noninfarcted myocardium in MI rats compared with sham-operated animals. Phosphorylation of MAPKK 3/6 (MKK3/6) and p38 MAPK, the downstream targets of TAK1, was also increased in the noninfarcted region. Moreover, an in vitro kinase assay revealed that the activated TAK1 in the noninfarcted myocardium was capable of activating recombinant MKK3/6, suggesting a causative role of TAK1 in the remodeling process. The activation of the TGF-1-TAK1-p38 MAPK pathway paralleled the transcriptional upregulation of cardiac markers for ventricular hypertrophy, -myosin heavy chain and atrial natriuretic peptide. TAK1 was mainly localized to cardiomyocytes, whereas TGF-1 receptors were observed in vascular smooth muscle cells and fibroblasts as well as cardiomyocytes. Thus the TGF-1-TAK1-MKK3/6-p38 MAPK pathway in the cardiomyocytes of noninfarcted spared myocardium is activated after acute MI and may play an important role in ventricular hypertrophy and post-MI remodeling in rats.

signal transduction; cytokine; hypertrophy; transforming growth factor-1-activated kinase; mitogen-activated protein kinase

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