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mTOR mediates RhoA-dependent leptin-induced cardiomyocyte hypertrophy

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Abstract

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 (RhoA, Rac1, and Cdc42) and mammalian target of rapamycin (mTOR) have recently emerged as important regulators of cell growth. We therefore explored the roles and interrelationships of phosphatidylinositol 3-kinase (PI3K), mTOR, and the Rho family in the regulation of actin polymerization and leptin-induced hypertrophy in cultured neonatal rat ventricular myocytes. Five minutes treatment with leptin (3.1 nM) resulted in activation of RhoA and Rac1 (by 330 and 160%, respectively, P < 0.05) which was significantly attenuated by AG-490 (50 μM) and LY294002 (10 μM), specific inhibitors of JAK2 and PI3K, respectively. However, Cdc42 activity was unaffected by leptin. The hypertrophic effect of leptin was associated with an increase in phosphorylation of p70S6K, the major target of mTOR, by 110% (P < 0.05). The specific mTOR inhibitor rapamycin (10 nM) attenuated leptin-induced RhoA and Rac1 activation. Furthermore, the leptin-induced decrease in the G/F-actin ratio, a measure of actin polymerization, was blunted by rapamycin. Leptin produced activation of the transcriptional factor GATA4 which was attenuated by the RhoA inhibitor C3, the p38 MAPK inhibitor SB203580 (10 μM) as well as rapamycin. Our results demonstrate a critical role for PI3K/mTOR/p70S6K in leptin-induced RhoA activation resulting in cardiomyocyte hypertrophy associated with GATA4 stimulation.

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Acknowledgments

This work was supported by Grant No. MOP 62764 from the Canadian Institutes of Health Research. M. Karmazyn holds a Canada Research Chair in Experimental Cardiology.

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Author notes

  1. Asad Zeidan

    Present address: Department of Physiology, American University of Beirut, Beirut, Lebanon

  2. J. Craig Hunter

    Present address: Department of Kinesiology, Pennsylvania State University, University Park, PA, 16802, USA

  3. Sabzali Javadov

    Present address: Department of Physiology, University of Puerto Rico School of Medicine, San Juan, PR, 00936-5067, USA

Authors and Affiliations

  1. Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada

    Asad Zeidan, J. Craig Hunter, Sabzali Javadov & Morris Karmazyn

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  1. Asad Zeidan
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Correspondence to Morris Karmazyn.

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Zeidan, A., Hunter, J.C., Javadov, S. et al. mTOR mediates RhoA-dependent leptin-induced cardiomyocyte hypertrophy. Mol Cell Biochem 352, 99–108 (2011). https://doi.org/10.1007/s11010-011-0744-2

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  • DOI: https://doi.org/10.1007/s11010-011-0744-2

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