Load-induced transcriptional activation of c-jun in rat myocardium - Regulation by myocyte enhancer factor 2

Autor(es)

Nadruz Júnior, Wilson ^[1] ; Kobarg, Claudia B. ; Constancio, Sábata S. ; Corat, Patrícia D. C. ; Franchini, Kleber G. ^[5]

Afiliação do(s) autor(es)

^[1] Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas - Brasil

^[5] Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas. Departamento de Clínica Médica - Brasil

• Tipo de documento: Artigo Científico
• Fonte: Circulation Research; v. 92, n. 2, p. 243-251, Feb. 2003.
• Área do conhecimento: Ciências da Saúde - Medicina
• Assunto(s): Sistema cardiovascular Miocárdio Células musculares Fatores de transcrição Genes jun Proteína quinase 7 ativada por mitógeno

Resumo

The increased expression of immediate-early genes is a key feature of the myocardial response to hypertrophic stimuli. In this study, we investigated whether pressure overload or phenylephrine treatment stimulated myocyte enhancer factor 2 (MEF2)-dependent transcriptional activation of c-jun in cardiac myocytes. Western blotting and immunohistochemical analysis of rat myocardium demonstrated that p70MEF2 is highly expressed in the rat heart and is predominantly located at the nuclei of cardiac myocytes. Electrophoretic mobility shift assays of myocardial nuclear extracts revealed a consistent DNA binding activation of MEF2 after 1 and 2 hours of pressure overload. We further showed that pressure overload induced a progressive nuclear translocation and activation of extracellular signal-regulated kinase 5 (ERK5). Coimmunoprecipitation and in vitro kinase assays indicated that the activation of ERK5 was paralleled by increased association of ERK5/p70MEF2 and by enhanced ability of ERK5 to phosphorylate p70MEF2. Experiments with in vivo transfection of the left ventricle with the c-jun promoter reporter gene showed that pressure overload induced a consistent increase of c-jun transcriptional activity in the rat myocardium. Rendering the MEF2 site of the c-jun plasmid inactive by mutation abolished the load-induced activation of the c-jun promoter reporter gene. Mutation of the MEF2 site also abolished the phenylephrine-induced c-jun promoter activation in neonatal rat ventricular myocytes. In addition, we demonstrated that neonatal rat ventricular myocyte transfection with ERK5-antisense oligodeoxynucleotide inhibited the phenylephrine-induced c-jun promoter activation. These findings identify MEF2 as a potential regulator of c-jun transactivation and suggest that ERK5 might be an important mediator of MEF2 and c-jun promoter activation in response to hypertrophic stimuli in cardiac myocytes. (AU)

• Processo FAPESP: 99/10263-0 - Sinalizacao celular durante aumento de tensao no coracao: ativacao e regulacao de vias celulares de crescimento cardiaco.
• Beneficiário: Wilson Nadruz Junior
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 00/03542-9 - Perfil de expressão gênica em cardiomiócitos de rato em cultura, submetidos à sobrecarga mecânica por estiramento
• Beneficiário: Kleber Gomes Franchini
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 01/11698-1 - Mecanismos de sinalização celular ativados por sobrecarga mecânica: implicações na hipertrofia e remodelamento miocárdicos
• Beneficiário: Kleber Gomes Franchini
• Modalidade de apoio: Auxílio à Pesquisa - Temático