Abstract 347: Targeted FAK Activation in Cardiomyocytes Protects the Heart from Doxorubicin-Induced Cardiomyopathy

Abstract

OBJECTIVE: We recently reported that cardiac-restricted activation of focal adhesion kinase (FAK) attenuated myocardial injury following ischemia/reperfusion using transgenic mice that express a FAK variant (termed SuperFAK) in cardiomyocytes. Here we interrogated whether targeted elevation of myocardial FAK activity could protect against cardiomyopathy induced by the highly effective chemotherapy drug Doxorubicin (DOX). METHODS AND RESULTS: Eight- to twelve-week-old male mice were given a single injection of DOX (20mg/kg, i.p.). At day 14, SuperFAK mice exhibited better survival (62.5%, n=8) than littermate control mice (37.5%, n=8). Serial echocardiography revealed that DOX administration markedly decreased cardiac function and ventricular wall thickness in control mice, whereas both parameters were better preserved in SuperFAK mice at day 5 (fractional shortening: 52.7±1.5% in SuperFAK vs . 38.9±3.7% in control, p <0.01; posterior wall end-systolic thickness: 1.83±0.12mm in SuperFAK vs . 1.43±0.12mm in control, p <0.05). Importantly, SuperFAK hearts exhibited a dramatic increase in FAK activity (as assessed by phospho-FAK Y397 immunoblotting) and a reduction in myocyte apoptosis (as assessed by TUNEL staining) in comparison with control hearts. DOX also induced apoptosis in cultured neonatal rat cardiomyocytes and adenoviral-mediated expression of SuperFAK ameliorated DOX-induced toxicity as assessed by MTT and TUNEL assays. Over-expression of SuperFAK also enhanced expression of the pro-survival NF-κB transcriptional targets Bcl-2, Bcl-xl, and X-linked inhibitor of apoptosis, whereas pharmacologically blockade of the NF-κB pathway completely abolished the up-regulation of these anti-apoptotic molecules by SuperFAK. CONCLUSIONS: Ventricular dysfunction and myocyte apoptosis induced by DOX was attenuated by enhancing cardiac FAK activity, which may represent a novel strategy to reduce anthracycline mediated cardiotoxicity in cancer patients undergoing chemotherapy.