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RhoA links PI3K/Akt/mTOR signaling to p38 MAPK/GATA‐4 activation in leptin–induced cardiomyocyte hypertrophy
Author(s) -
Zeidan Asad,
Hunter Craig,
Javadov Sabzali,
Karmazyn Morris
Publication year - 2009
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.23.1_supplement.577.7
Subject(s) - rhoa , leptin , pi3k/akt/mtor pathway , protein kinase b , p70 s6 kinase 1 , medicine , endocrinology , chemistry , mapk/erk pathway , phosphorylation , microbiology and biotechnology , biology , signal transduction , obesity
Obesity is associated with increased leptin production which may contribute to cardiac hypertrophy. However, the mechanism of leptin‐induced cardiac hypertrophy remains incompletely understood. The Rho family and mTOR have recently emerged as important regulators of cell growth. In this study we explored the roles of phosphatidylinositol 3‐kinase (PI3K), mTOR and the Rho family in the regulation of actin polymerization in leptin‐induced hypertrophy in cultured neonatal rat cardiomyocytes treated with 3.1 nM leptin. Leptin treatment resulted in activation of RhoA and Rac1 (by 330% and 160%, respectively; P<0.05) but not cdc42, 5 min after treatment, as determined by Western blotting. The hypertrophic effect of leptin was associated with an increase in phosphorylation of p70 S6K by 110% (P<0.05). The specific mTOR inhibitor, rapamycin (10 nM) attenuated leptin‐induced RhoA and Rac1 activation. Furthermore, the decrease in the G/F actin ratio, a measure of actin polymerization, was blunted by rapamycin. Leptin produced activation of the transcriptional factor GATA‐4 which was attenuated by the RhoA inhibitor C3, the p38 MAPK inhibitor SB203580 (10 µM) or rapamycin. Our results demonstrate that leptin‐induced cardiomyocyte hypertrophy is associated with GATA‐4 activation which is dependent on RhoA, PI3K/mTOR/p70 S6K and p38 MAPK pathways. Supported by the Canadian Institutes of Health Research.