title: 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.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Melissa
authors.initials: M
authors.lastname: Moey
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Rajapurohitam
authors.forename: Asad
authors.initials: A
authors.lastname: Zeidan
authors.forename: Morris
authors.initials: M
authors.lastname: Karmazyn
mesh_terms: D000199:Actins / Q000187:drug effects / Q000502:physiology; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D051340:Cofilin 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D020738:Leptin / Q000037:antagonists & inhibitors / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005894:Panax; D010766:Phosphorylation / Q000187:drug effects; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D018517:Plant Roots; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D002316:Cardiotonic Agents; D051340:Cofilin 2; D020662:Guanine Nucleotide Exchange Factors; D020738:Leptin; D010936:Plant Extracts; D054411:Receptors, Leptin; D064067:Rho Guanine Nucleotide Exchange Factors; D054460:rho-Associated Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein