Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice

Autor(es)

Clemente, Carolina F. M. Z. ^[1] ; Tornatore, Thais F. ; Theizen, Thais H. ; Deckmann, Ana C. ; Pereira, Tiago C. ; Lopes-Cendes, Iscia ; Souza, José Roberto M. ; Franchini, Kleber G. ^[8]

Afiliação do(s) autor(es)

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

^[8] Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas. Departamento de Clínica Médica - Brasil

• Tipo de documento: Artigo Científico
• Fonte: Circulation Research; v. 101, n. 12, p. 1339-1348, Dec. 2007.
• Área do conhecimento: Ciências da Saúde - Medicina
• Notas: O artigo consta como produto de dois processos: 01/11698-1 em nome de Kleber Gomes Franchini; 04/10167-0 em nome de Carolina Fernanda Manfredi Zambon Clemente
• Assunto(s): Sistema cardiovascular Doenças cardiovasculares Insuficiência cardíaca Miócitos cardíacos Transdução de sinais

Resumo

Hypertrophy is a critical event in the onset of failure in chronically overloaded hearts. Focal adhesion kinase (FAK) has attracted particular attention as a mediator of hypertrophy induced by increased load. Here, we demonstrate increased expression and phosphorylation of FAK in the hypertrophic left ventricles (LVs) of aortic-banded mice. We used an RNA interference strategy to examine whether FAK signaling plays a role in the pathophysiology of load-induced LV hypertrophy and failure. Intrajugular delivery of specific small interfering RNA induced prolonged FAK silencing (70%) in both normal and hypertrophic LVs. Myocardial FAK silencing was accompanied by prevention, as well as reversal, of load-induced left ventricular hypertrophy. The function of LVs was preserved and the survival rate was higher in banded mice treated with small interfering RNA targeted to FAK, despite the persistent pressure overload. Studies in cardiac myocytes and fibroblasts harvested from LVs confirmed the ability of the systemically administered specific small interfering RNA to silence FAK in both cell types. Further analysis indicated attenuation of cardiac myocyte hypertrophic growth and of the rise in the expression of BETA-myosin heavy chain in overloaded LVs. Moreover, FAK silencing was demonstrated to attenuate the rise in the fibrosis, collagen content, and activity of matrix metalloproteinase-2 in overloaded LVs, as well as the rise of matrix metalloproteinase-2 protein expression in fibroblasts harvested from overloaded LVs. This study provides novel evidence that FAK may be involved in multiple aspects of the pathophysiology of cardiac hypertrophy and failure induced by pressure overload. (AU)

• 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
• Processo FAPESP: 04/10167-0 - Influência da quinase de adesão focal na hipertrofia miocárdica induzida por sobrecarga pressora em corações de camundongos
• Beneficiário: carolina fernanda manfredi zambon clemente
• Modalidade de apoio: Bolsas no Brasil - Doutorado