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dc.contributor.CRUESPUniversidade Estadual de Campinaspt_BR
dc.typeArtigo de periódicopt_BR
dc.titleFAK mediates the activation of cardiac fibroblasts induced by mechanical stress through regulation of the mTOR complexpt_BR
dc.contributor.authorDalla Costa, APpt_BR
dc.contributor.authorClemente, CFMZpt_BR
dc.contributor.authorCarvalho, HFpt_BR
dc.contributor.authorCarvalheira, JBpt_BR
dc.contributor.authorNadruz, Wpt_BR
dc.contributor.authorFranchini, KGpt_BR
unicamp.authorUniv Estadual Campinas, Dept Cell Biol, Campinas, SP, Brazil Univ Estadual Campinas, Sch Med, Dept Internal Med, Campinas, SP, Brazilpt_BR
dc.subjectCell proliferationpt_BR
dc.subjectCell differentiationpt_BR
dc.subjectCell stretchpt_BR
dc.subjectHeart failurept_BR
dc.subject.wosFocal Adhesion Kinasept_BR
dc.subject.wosMyofibroblast Differentiationpt_BR
dc.subject.wosMapk Activationpt_BR
dc.subject.wosCell Motilitypt_BR
dc.subject.wosCyclin D1pt_BR
dc.description.abstractCardiac fibroblasts are activated by mechanical stress, but the underlying mechanisms involved remain poorly understood. In this study, we investigated whether focal adhesion kinase (FAK) plays a role in the activation of cardiac fibroblasts in response to cyclic stretch. Neonatal (NF-P3/80-third passage, 80% confluence) and adult (AF-P1/80-first passage, 80% confluence) rat cardiac fibroblasts were exposed to cyclic stretch (biaxial, 1 Hz), which enhanced FAK phosphorylation at Tyr397. Proliferation (anti-5-bromo-2'-deoxyuridine and anti-Ki67 nuclear labelling), differentiation into myofibroblasts (expression of alpha-smooth muscle actin-alpha-SMA), and the activity of matrix metalloproteinase-2 were equally enhanced in stretched NF-P3/80 and AF-P1/80. Treatment with the integrin inhibitor RGD peptide impaired FAK phosphorylation and increased apoptosis (TUNEL) in non-stretched and stretched NF-P3/80, whereas FAK silencing induced by small interfering RNA modestly enhanced apoptosis only in stretched cells. RGD peptide or FAK silencing suppressed the activation of NF-P3/80 invoked by cyclic stretch. In addition, NF-P3/80 depleted of FAK were defective in AKT Ser473, TSC-2 Thr1462, and S6 kinase Thr389 phosphorylation induced by cyclic stretch. The activation of NF-P3/80 invoked by cyclic stretch was prevented by pre-treatment with the mammalian target of rapamycin (mTOR) inhibitor rapamycin, whereas supplementation with the amino acid, leucine, activated S6K and rescued the stretch-induced activation of NF-P3/80 depleted of FAK. These findings demonstrate a critical role for the mTOR complex, downstream from FAK, in mediating the activation of cardiac fibroblasts in response to mechanical
dc.relation.ispartofCardiovascular Researchpt_BR
dc.relation.ispartofabbreviationCardiovasc. Res.pt_BR
dc.publisherOxford Univ Presspt_BR
dc.identifier.citationCardiovascular Research. Oxford Univ Press, v. 86, n. 3, n. 421, n. 431, 2010.pt_BR
dc.sourceWeb of Sciencept_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.description.sponsorshipLaboratorio Cristaliapt_BR
dc.description.sponsorship1Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorship1Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.description.sponsordocumentnumberFAPESP [2006/54878-3]pt
dc.description.sponsordocumentnumberCNPq [305604/2006-6, 474650/2006-5]pt
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