TGF-β1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation

Joong Yeon Lim, Joon Park Sung, Ha Young Hwang, Jung Park Eun, Hwan Nam Jae, Joon Kim, Sang Ick Park

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Several reports have suggested that the TAK1-MKK3/6-p38MAPK signaling axis is important for TGF-β-related cardiac hypertrophy. Despite this, the effects of exogenous TGF-β on cardiac hypertrophy and associated signaling mechanisms have not been demonstrated directly. Moreover, the roles of the signaling mechanisms involved in cardiac hypertrophy (TAK1 upstream and p38MAPK downstream) remain unclear. In this study, we investigated the potential involvement of protein kinase C and activating transcription factor-2 in TGF-β1-induced cardiac hypertrophic responses in cultured neonatal rat ventricular cardiomyocytes. TGF-β1 treatment resulted in upregulation of mRNA expression or promoter activities of β-myosin heavy chain, atrial natriuretic factor, and brain natriuretic peptide, and increased myocyte protein content, cell size, and sarcomeric organization. These are all characteristic hallmarks of cardiac hypertrophy. PKC was found to be involved throughout the signaling system, and it was shown that it acts by mediating upstream TAK1 activation and leads to ATF-2 activation. PKC-dependent ATF-2 activation was shown to be involved in TGF-β1-induced cardiac hypertrophic responses. The PKC inhibitors, GO6976 and GF109203X, completely blocked TGF-β1-induced TAK1 kinase activity and subsequent downstream signaling pathways including ATF-2 phosphorylation, leading to suppression of ATF-2 transcriptional activity. This inhibitory effect was reflected in cardiac hypertrophic responses such as inhibitions of β-MHC gene induction and ANF promoter activity. Our results suggest that PKC is involved in TGF-β1-induced cardiac hypertrophic responses in our cell culture system and that ATF-2 activation plays a role.

Original languageEnglish
Pages (from-to)627-636
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume39
Issue number4
DOIs
Publication statusPublished - 2005 Oct

Keywords

  • Cytokine
  • Hypertrophy
  • MAP kinase
  • Myocyte
  • Protein phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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