Importance of local adhesion kinase signaling in the cardiac hypertrophy induced by pressure overload in mice

Author(s)

Carolina Fernanda Manfredi Zambon Clemente

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2008-03-07

Examining board members

Kleber Gomes Franchini; Lusiane Maria Bendhack; Everardo Magalhães Carneiro; Wilson Nadruz Junior

• Advisor: Kleber Gomes Franchini

Abstract

Hypertrophy is a critical event in the onset of failure in chronically overloaded hearts. Mechanical stress and neurohumoral factors signaling factors have been considered the main triggering stimuli for the installation of hypertrophy in cardiac myocytes in a variety of pathological process. In this context, focal adhesion kinase (FAK), a key protein of the integrin signaling pathway, has attracted particular attention as a mediator of hypertrophy induced by increased load. This study was performed to address the influence of FAK in the pathophysiology of cardiac hypertrophy and failure induced by chronic pressure overload in mice using RNA interference methodology. Aortic constriction in mice induced left ventricle (LV) hypertrophy and increased expression and phosphorylation of FAK. Intrajugular delivery of specific small interfering RNA induced prolonged FAK silencing (~70%) in both normal and hypertrophic LVs. 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. 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. Further analysis indicated attenuation of cardiac myocyte hypertrophic growth and of the rise in the expression of ß-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 indicate that FAK is necessary not only to the development but also to sustain LV hypertrophy in response to chronic pressure overload (AU)