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.
Footnotes
This work was supported by the Canadian Institutes of Health Research [Grant MOP 62764]; and the Ontario Ginseng Innovation and Research Consortium. M.M. was supported by the Ontario Ginseng Innovation and Research Consortium. M.K. holds a Tier 1 Canada Research Chair in Experimental Cardiology.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.182600.
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ABBREVIATIONS:
- RhoA
- Ras homolog gene family, member A
- ROCK
- Rho-associated, coiled-coil containing protein kinase
- α-SA
- α-skeletal actin
- GEF
- guanine nucleotide exchange factor
- F actin
- filamentous actin
- G actin
- globular actin
- ERK1/2
- extracellular signal-related kinase 1/2
- MAPK
- mitogen-activated protein kinase
- Ob-Rb
- leptin receptor isoform b
- PCR
- polymerase chain reaction
- PBS
- phosphate-buffered saline
- BSA
- bovine serum albumin.
- Received April 1, 2011.
- Accepted August 25, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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