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

Matsumoto-Ida, Madoka, Yoshihito Takimoto, Takeshi Aoyama, Masaharu Akao, Toshihiro Takeda, and Toru Kita. Activation of TGF1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol 290: H709–H715, 2006. First published September 23, 2005; doi:10.1152/ajpheart.00186.2005.—Transforming growth factor1 (TGF1) 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 TGF1TAK1-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, TGF1, TGFreceptors, 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 TGF1-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 TGF1 receptors were observed in vascular smooth muscle cells and fibroblasts as well as cardiomyocytes. Thus the TGF1-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.