Role of Rho‐mediated processes and intact actin cytoskeleton in leptin induced cardiomyocytes hypertrophy

Abstract

Obesity is associated with increased leptin production which may contribute to cardiac hypertrophy. Although leptin has been shown to produce cardiomyocyte hypertrophy, its mechanism of action is unknown. Activation of Rho A has been shown to be associated with cardiac pathology and we therefore determined the role of Rho/ROCK as mediators of leptin induced cell hypertrophy in cultured neonatal rat myocytes. Leptin (3.1 nM) significantly increased cell size by 32 ± 5% and leucine incorporation by 42 ± 7%. These effects were associated with significant activation of Rho A (254 ± 25%) which was significantly attenuated by the coadministration of an anti-leptin antibody (166 ng/ml) to 70 ± 20% of control values. Both the Rho A inhibitor C3 exoenzyme and ROCK inhibitor Y27632, potently attenuated leptin-induced increased cell size and leucine incorporation. The hypertrophic effect of leptin was associated with a 190 ± 20% increase in phosphorylation of cofilin, an actin binding protein. In addition, the increase in polymerization of actin resulted in a decreased G/F actin ratio which was significantly inhibited by both the anti-leptin antibody and Y-27632. Leptin-induced hypertrophy was also attenuated by disruption of actin filaments with 50 nM latrunculin B. Our results indicate that the activation of Rho and actin dynamics plays an important role in the leptin signaling leading to the development of cell hypertrophy. This study is supported by HSFO.