An essential role of Nrf2 in American ginseng-mediated anti-oxidative actions in cardiomyocytes

A growing body of evidence has revealed that regular use of ginseng is helpful in the treatment of cardiovascular diseases; however, the underlying mechanisms are not fully understood. Our results indicate for the first time that activation of Nrf2 signaling is likely to be a crucial common pathway...

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Bibliographic Details
Published in:Journal of ethnopharmacology 2010-07, Vol.130 (2), p.222-230
Main Authors: Li, Jinqing, Ichikawa, Tomonaga, Jin, Yu, Hofseth, Lorne J., Nagarkatti, Prakash, Nagarkatti, Mitzi, Windust, Anthony, Cui, Taixing
Format: Article
Language:English
Subjects:
Administration, Oral
American ginseng
Angiotensin II - metabolism
Animals
antioxidant activity
antioxidants
Antioxidants - administration & dosage
Antioxidants - pharmacology
biochemical pathways
Biological and medical sciences
Cardiomyocytes
cardioprotective effect
cardiovascular agents
cardiovascular diseases
Cell Death
Cell Line
Dose-Response Relationship, Drug
gene expression
Gene Expression Regulation
General pharmacology
heart
herbal medicines
Humans
Hydrogen Peroxide - pharmacology
in vitro studies
inhibitors
leucine zipper
Male
Medical sciences
medicinal plants
Mice
Mice, Inbred C57BL
myocytes
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Nrf2
Oxidants - pharmacology
Oxidative stress
Oxidative Stress - drug effects
Panax
Panax quinquefolius
Pharmacognosy. Homeopathy. Health food
Pharmacology. Drug treatments
Plant Extracts - administration & dosage
Plant Extracts - pharmacology
protein synthesis
Rats
RNA Interference
Time Factors
transcription factors
Tumor Necrosis Factor-alpha - metabolism
Up-Regulation
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Summary:A growing body of evidence has revealed that regular use of ginseng is helpful in the treatment of cardiovascular diseases; however, the underlying mechanisms are not fully understood. Our results indicate for the first time that activation of Nrf2 signaling is likely to be a crucial common pathway for the ginseng-mediated cardiac protective actions. Ginseng has been used as a folk medicine for thousands of years in Asia, and has become a popular herbal medicine world-wide. Recent studies have revealed that ginseng, including American ginseng, exerts antioxidant effects in the cardiovascular system; however, the underlying mechanisms are not fully understood. Thus, we investigated role of Nrf2, a master transcription factor of endogenous anti-oxidative defense systems, in the regulation of American ginseng-mediated anti-oxidative actions in cardiomyocytes. A standardized crude extract of American ginseng was supplied by the National Research Council of Canada, Institute for National Measurement Standards. H9C2 cells, a rat cardiomyocyte cell line, were exposed to angiotensin II (Ang II) or tumor necrosis factor alpha (TNFα) to induce oxidative stress that was examined by measuring formation of reactive oxygen and nitrogen species. Oxidative stress-induced cell death was induced by exogenous addition of hydrogen peroxide (H 2O 2). Proteins were measured by Western blot and mRNA expression was determined by quantitative real time PCR. Nrf2-driven transcriptional activity was assessed by antioxidant response element (ARE)-luciferase reporter assay. Direct Nrf2 binding to its target gene promoters was determined by chromatin immunoprecipitation assay. Adenoviral over-expression of Nrf2 shRNA was utilized to knock down Nrf2 in H9C2 cells. Immunochemical staining was applied for Nrf2 expression in the heart. American ginseng induced dramatic increases in Nrf2 protein expression, Nrf2 nuclear translocation, Nrf2 transcriptional activity, direct Nrf2 binding to its target gene promoters, and expression of a group of anti-oxidative genes driven by Nrf2 in H9C2 cells. In addition, American ginseng inhibited Ang II- or TNFα-induced free radical formation and H 2O 2-induced cell death in H9C2 cells over-expressed with control shRNA but not in the cells over-expressed with Nrf2 shRNA. Finally, oral administration of American ginseng markedly increased Nrf2 activity in murine hearts. These results demonstrate that American ginseng suppresses oxidative stress and oxidati
ISSN:0378-8741
1872-7573
DOI:10.1016/j.jep.2010.03.040