Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress

Pharmacol Res. 2006 Jan;53(1):6-15. doi: 10.1016/j.phrs.2005.08.002. Epub 2005 Oct 5.


Resveratrol (3,4',5-trihydroxystilbene), a polyphenolic compound found in mulberries, grapes and red wine has been demonstrated to be capable of protecting against oxidative cardiovascular pathophysiology. However, the underlying cellular and biochemical mechanisms remain to be elucidated. This study was undertaken to determine if resveratrol could upregulate endogenous antioxidants and phase 2 enzymes in cultured aortic smooth muscle cells (ASMCs), and if such increased cellular defenses could provide protection against oxidative and electrophilic vascular cell injury. Incubation of rat ASMCs with resveratrol at low micromolar concentrations resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time-dependent fashion. These cytoprotective factors include superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase, glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NOQ1). Notably, induction of catalase, GST, and NOQ1 was most remarkable among the above resveratrol-inducible antioxidants and phase 2 enzymes. Moreover, resveratrol treatment also significantly increased the mRNA expression of catalase, GSTA1, and NQO1 in a time-dependent manner. Pretreatment of ASMCs with resveratrol afforded a remarkable protection against xanthine oxidase (XO)/xanthine- or 4-hydroxy-2-nonenal-induced cytotoxicity, as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Resveratrol pretreatment also led to a marked reduction in intracellular accumulation of reactive oxygen species in ASMCs after incubation with XO/xanthine. Taken together, this study demonstrates that a scope of key endogenous antioxidants and phase 2 enzymes in cultured ASMCs can be upregulated by resveratrol at low micromolar concentrations, and that such chemically-elevated cellular defenses rendered cells increased resistance to oxidative and electrophilic stress. The results of this study thus suggested a new mechanism, which might contribute to the cardiovascular protective effects of resveratrol.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldehydes / toxicity
  • Animals
  • Antioxidants / metabolism*
  • Aorta / cytology
  • Catalase / genetics
  • Catalase / metabolism
  • Cells, Cultured
  • Cytoprotection
  • Glutathione / metabolism
  • Glutathione Peroxidase / metabolism
  • Glutathione Reductase / metabolism
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / enzymology
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / enzymology
  • Myocytes, Smooth Muscle / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Oxidative Stress
  • Rats
  • Reactive Oxygen Species / metabolism
  • Resveratrol
  • Stilbenes / pharmacology*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Up-Regulation
  • Wine
  • Xanthine Oxidase / toxicity


  • Aldehydes
  • Antioxidants
  • Isoenzymes
  • Reactive Oxygen Species
  • Stilbenes
  • Catalase
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • Xanthine Oxidase
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, rat
  • Glutathione Reductase
  • Glutathione Transferase
  • glutathione S-transferase alpha
  • Glutathione
  • 4-hydroxy-2-nonenal
  • Resveratrol