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1 Internal Medicine, State University of Campinas, School of Medicine, Campinas, SP, Brazil
* To whom correspondence should be addressed. E-mail: franchin{at}unicamp.br.
FAK (focal adhesion kinase) has been shown to be activated in cardiac myocytes exposed to mechanical stress. However, details of how mechanical stimuli induce Fak activation are unknown. Here, we investigated whether signaling events mediated by RhoA/ROCK pathway are involved in the regulation of stretch-induced FAK phosphorylation at Tyr-397 in neonatal rat ventricular myocytes (NRVMs). Immunostaining showed that RhoA localized to regions of myofilaments alternated with phalloidin (actin) staining. The results of co-immunoprecipitation assays indicated that Fak and RhoA are associated in non-stretched NRVMs, but cyclic stretch significantly reduced the amount of RhoA recovered from anti-Fak immunoprecipitates. Cyclic stretch induced rapid and sustained (up to 2 hours) increases of Fak Tyr397 and Erk1/2 Thr202/Tyr204 phosphorylation. Blockade of RhoA/ROCK signaling by pharmacological inhibitors of RhoA (C. botulinum C3-Exoenzyme) or ROCK (Y-27632; 10 µmol/l, 1 h) markedly attenuated the stretch-induced Fak and Erk1/2 phosphorylation. Similar effects were observed in cells treated with the inhibitor of actin polymerization, cytochalasin D. Transfection of NRVMs with RhoA antisense oligonucleotide attenuated the stretch-induced Fak and Erk1/2 phosphorylation and the expression of 
-myosin heavy chain mRNA. Similar results were seen in cells transfected with FAK antisense oligonucleotide. These findings demonstrate that RhoA/ROCK signaling plays a crucial role in stretch-induced Fak phosphorylation, presumably by coordinating upstream events operationally linked to actin cytoskeleton.
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