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FAK mediates the activation of cardiac fibroblasts induced by mechanical stress through regulation of mTOR complex
Author(s) -
Dalla Costa Ana Paula,
Clemente Carolina F.M.Z,
Carvalho Hernandes Faustino,
Carvalheira José B.,
Franchini Kleber G.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.644.5
Subject(s) - focal adhesion , pi3k/akt/mtor pathway , chemistry , microbiology and biotechnology , protein kinase b , integrin , myofibroblast , stress fiber , p70 s6 kinase 1 , kinase , signal transduction , cancer research , biology , medicine , receptor , biochemistry , fibrosis
We evaluated whether focal adhesion kinase (FAK) plays a role in the proliferation and differentiation of cardiac fibroblasts into myofibroblasts in response to cyclic stretch (CS). Neonatal (NF‐ 3 rd passage, 80% confluence) and adult (AF– 1 st passage, 80% confluence) rat cardiac fibroblasts were exposed to CS (biaxial, 1Hz), which enhanced phospho‐FAK Y397 . Proliferation (anti‐Ki67 nuclear), differentiation into myofibroblasts (expression of α‐smooth muscle actin –α‐SMA) and the activity of matrix metalloproteinase‐2 (MMP‐2) were equally enhanced in stretched NF‐P3/80 and AF‐P1/80. Assays with the integrin inhibitor RGD peptide increased apoptosis (TUNEL) in non‐stretched and stretched NF‐P3/80, while FAK knockdown induced by siRNA modestly enhanced apoptosis only in stretched cells. RGD peptide or FAK silencing suppressed the activation of NF‐P3/80 invoked by CS. NF‐P3/80 depleted of FAK were defective in phospho‐AKT S473 , TSC‐2 T1462 , and S6 kinase T389 induced by CS. The activation of NF‐P3/80 invoked by CS was prevented by pre‐treatment with rapamycin, the mammalian target of rapamycin (mTOR) inhibitor, whereas treatment with 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, FAK downstream, in mediating the activation of cardiac fibroblasts in response to mechanical stress.