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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

RETRACTED: FAK mediates the activation of cardiac fibroblasts induced by mechanical stress through regulation of the mTOR complex (Retracted article. See vol. 104, pg. 512, 2014)

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Dalla Costa, Ana Paula [1] ; Clemente, Carolina F. M. Z. [1] ; Carvalho, Hernandes F. [1] ; Carvalheira, Jose B. [1] ; Nadruz, Jr., Wilson [1] ; Franchini, Kleber G. [1]
Total Authors: 6
[1] Univ Estadual Campinas, Sch Med, Dept Internal Med, Campinas, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: Cardiovascular Research; v. 86, n. 3, p. 421-431, JUN 1 2010.
Web of Science Citations: 37

Cardiac 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 stress. (AU)

FAPESP's process: 06/54878-3 - Pathogenesis of cardiac hypertrophy and failure: mechanisms activated by mechanical stress
Grantee:Kleber Gomes Franchini
Support type: Research Projects - Thematic Grants