TY - JOUR
T1 - TGF-β1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation
AU - Lim, Joong Yeon
AU - Sung, Joon Park
AU - Hwang, Ha Young
AU - Eun, Jung Park
AU - Jae, Hwan Nam
AU - Kim, Joon
AU - Park, Sang Ick
PY - 2005/10
Y1 - 2005/10
N2 - 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.
AB - 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.
KW - Cytokine
KW - Hypertrophy
KW - MAP kinase
KW - Myocyte
KW - Protein phosphorylation
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U2 - 10.1016/j.yjmcc.2005.06.016
DO - 10.1016/j.yjmcc.2005.06.016
M3 - Article
C2 - 16125722
AN - SCOPUS:24944542831
SN - 0022-2828
VL - 39
SP - 627
EP - 636
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 4
ER -