title: TGF-beta1 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-beta-related cardiac hypertrophy. Despite this, the effects of exogenous TGF-beta 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-beta1-induced cardiac hypertrophic responses in cultured neonatal rat ventricular cardiomyocytes. TGF-beta1 treatment resulted in upregulation of mRNA expression or promoter activities of beta-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-beta1-induced cardiac hypertrophic responses. The PKC inhibitors, GO6976 and GF109203X, completely blocked TGF-beta1-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 beta-MHC gene induction and ANF promoter activity. Our results suggest that PKC is involved in TGF-beta1-induced cardiac hypertrophic responses in our cell culture system and that ATF-2 activation plays a role.
authors.affiliation: Division of Cardiovascular Diseases, Department of Biomedical Sciences, National Institute of Health, 5 Nokbun-Dong, Eunpyung-Gu, Seoul 122-701, South Korea.
authors.forename: Joong-Yeon
authors.initials: JY
authors.lastname: Lim
authors.forename: Sung Joon
authors.initials: SJ
authors.lastname: Park
authors.forename: Ha-Young
authors.initials: HY
authors.lastname: Hwang
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Jae Hwan
authors.initials: JH
authors.lastname: Nam
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
authors.forename: Sang Ick
authors.initials: SI
authors.lastname: Park
mesh_terms: D051698:Activating Transcription Factor 2; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002227:Carbazoles / Q000494:pharmacology; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D007211:Indoles / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051698:Activating Transcription Factor 2; D009320:Atrial Natriuretic Factor; D002227:Carbazoles; D017362:Cyclic AMP Response Element-Binding Protein; D007211:Indoles; D020930:MAP Kinase Kinase Kinases; D008301:Maleimides; D018995:Myosin Heavy Chains; D020097:Natriuretic Peptide, Brain; D011493:Protein Kinase C; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7; C497107:Atf2 protein, rat; C000594638:MYH7 protein, rat; C508962:Tgfb1 protein, rat; C081021:Go 6976; C070515:bisindolylmaleimide I