Ginseng (Panax quinquefolius) attenuates leptin-induced cardiac hypertrophy through inhibition of p115Rho guanine nucleotide exchange factor-RhoA/Rho-associated, coiled-coil containing protein kinase-dependent mitogen-activated protein kinase pathway activation

• Published in: The Journal of pharmacology and experimental therapeutics 2011-12, Vol.339 (3), p.746-756
• Main Authors: Moey, Melissa, Rajapurohitam, Venkatesh, Zeidan, Asad, Karmazyn, Morris
• Format: Article
• Language: English
• Subjects: Actins - drug effects; Actins - physiology; Animals; Cardiomegaly - drug therapy; Cardiomegaly - physiopathology; Cardiotonic Agents - pharmacology; Cofilin 2 - metabolism; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Heart Ventricles - drug effects; Heart Ventricles - enzymology; Heart Ventricles - physiopathology; Humans; Leptin - antagonists & inhibitors; Leptin - physiology; Mitogen-Activated Protein Kinases - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; p38 Mitogen-Activated Protein Kinases - metabolism; Panax; Phosphorylation - drug effects; Phytotherapy; Plant Extracts - pharmacology; Plant Roots; Rats; Rats, Sprague-Dawley; Receptors, Leptin - metabolism; Rho Guanine Nucleotide Exchange Factors; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.111.182600

Leptin is a 16-kDa peptide primarily derived from white adipocytes and is typically elevated in plasma of obese individuals. Although leptin plays a critical role in appetite regulation, leptin receptors have been identified in numerous tissues including the heart and have been shown to directly mediate cardiac hypertrophy through RhoA/ROCK (Ras homolog gene family, member A/Rho-associated, coiled-coil containing protein kinase)-dependent p38 mitogen-activated protein kinase (MAPK) activation; however, the basis for RhoA stimulation is unknown. Rho guanine nucleotide exchange factors (GEFs) catalyze the exchange of GDP for GTP resulting in Rho activation and may be the potential upstream factors mediating leptin-induced RhoA activation and therefore a potential target for inhibition. We investigated the effects of North American ginseng (Panax quinquefolius), reported to reduce cardiac hypertrophy, on RhoA/ROCK and MAPK activation in ventricular cardiomyocytes exposed to leptin (50 ng/ml) and the possible role of p115RhoGEF and p63RhoGEF in these responses. Leptin produced a robust hypertrophic response that was associated with RhoA/ROCK activation resulting in a significant increase in cofilin-2 phosphorylation and actin polymerization, the latter evidenced by a reduction in the G/F actin ratio. These effects were prevented by ginseng (10 μg/ml). The stimulation of RhoA/ROCK by leptin was associated with significantly increased p115RhoGEF gene and protein expression and exchange activity, all of which were completely prevented by ginseng. The ability of ginseng to prevent leptin-induced activation of RhoA/ROCK was further associated with diminished p38 MAPK activation and nuclear translocation. These results demonstrate a potent inhibitory effect of ginseng against leptin-induced cardiac hypertrophy, an effect associated with prevention of p115RhoGEF-RhoA/ROCK-dependent p38 MAPK activation.