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

70 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 1

Fingerprint

Cardiomegaly
Atrial Natriuretic Factor
Activating Transcription Factor 2
Myosin Heavy Chains
Brain Natriuretic Peptide
Cell Size
Cardiac Myocytes
Muscle Cells
Protein Kinase C
Phosphotransferases
Up-Regulation
Cell Culture Techniques
Phosphorylation
Messenger RNA
Genes
Proteins

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

TGF-β1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation. / Lim, Joong Yeon; Sung, Joon Park; Hwang, Ha Young; Eun, Jung Park; Jae, Hwan Nam; Kim, Joon; Park, Sang Ick.

In: Journal of Molecular and Cellular Cardiology, Vol. 39, No. 4, 01.10.2005, p. 627-636.

Research output: Contribution to journalArticle

Lim, Joong Yeon ; Sung, Joon Park ; Hwang, Ha Young ; Eun, Jung Park ; Jae, Hwan Nam ; Kim, Joon ; Park, Sang Ick. / TGF-β1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation. In: Journal of Molecular and Cellular Cardiology. 2005 ; Vol. 39, No. 4. pp. 627-636.
@article{c7fcb6d13388479f9ad68b49a52a22bc,
title = "TGF-β1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation",
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.",
keywords = "Cytokine, Hypertrophy, MAP kinase, Myocyte, Protein phosphorylation",
author = "Lim, {Joong Yeon} and Sung, {Joon Park} and Hwang, {Ha Young} and Eun, {Jung Park} and Jae, {Hwan Nam} and Joon Kim and Park, {Sang Ick}",
year = "2005",
month = "10",
day = "1",
doi = "10.1016/j.yjmcc.2005.06.016",
language = "English",
volume = "39",
pages = "627--636",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
number = "4",

}

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 - 2005/10/1

Y1 - 2005/10/1

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

UR - http://www.scopus.com/inward/record.url?scp=24944542831&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24944542831&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2005.06.016

DO - 10.1016/j.yjmcc.2005.06.016

M3 - Article

C2 - 16125722

AN - SCOPUS:24944542831

VL - 39

SP - 627

EP - 636

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

IS - 4

ER -