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Kleber Franchini
Role of FAK in Cardiac Hypertrophy and Failure: moving from signaling to therapeutic targeting.
 

Kleber G. Franchini
Dept of Internal Medicine
State University of Campinas
 

Cardiac hypertrophy, which is mostly driven by mechanical stress, is thought to set the stage for heart failure. Our studies demonstrated that FAK (Focal Adhesion Kinase), is rapidly activated in cardiomyocytes in response to mechanical stress. The stretch-induced FAK activation in cardiomyocytes is accompanied by autophosphorylation at Tyr-397 and cooperation with Src to recruit multiple downstream signaling complexes involved in the control of distinct cell functions. New insights concerning the mechanism of FAK activation by mechanical stress in cardiomyocytes were provided by our recent demonstration that inactive FAK interacts with C‑terminal portion of myosin heavy chain (MHC). The interaction with myosin was demonstrated to inhibit FAK activity implying that the interaction with MHC may mediate FAK activation by mechanical stress. Yet, FAK accumulates in the nucleus of stretched cardiomyocytes where it possibly contributes to the regulation of gene expression in response to mechanical stress. Indeed, our data indicate the interaction of FAK with MEF2 and PGC1a which may contribute to the control of the expression of genes coding for mitochondria and sarcoplasmic reticulum biogenesis. Finally, in cardiomyocytes, we have shown that activated FAK coordinates the stretch-induced expression of hypertrophic genetic program. The importance of this effect to the load-induced hypertrophic response was confirmed by experiments performed in mice treated with siRNA targeted to FAK. In addition, the myocardial FAK silencing was shown to prevent the deterioration of cardiac function in chronically overloaded hearts, implying that FAK targeting by synthetic siRNA may be a potential therapeutic tool to treat cardiovascular diseases.
 
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