Red wine polyphenols enhance endothelial nitric oxide synthase expression and subsequent nitric oxide release from endothelial cells

Circulation. 2002 Sep 24;106(13):1614-7. doi: 10.1161/01.cir.0000034445.31543.43.


Background: Population-based studies suggest a reduced incidence of morbidity and mortality from coronary heart disease caused by moderate and regular consumption of red wine. Endothelial nitric oxide (NO) is a pivotal vasoprotective molecule. This study examines the influence of red wine polyphenols on the regulation of endothelial nitric oxide synthase (eNOS) expression and subsequent NO synthesis, focusing on the putative long-lasting antiatherosclerotic effects of red wine.

Methods and results: Treatment (20 hours) of human umbilical vein endothelial cells (HUVECs) and of the HUVEC-derived cell line EA.hy926 with a alcohol-free red wine polyphenol extract (RWPE) led to a concentration-dependent (100 to 600 microg/mL), significant increase in NO release (up to 3.0-fold/HUVEC and 2.0-fold/EA.hy926) as shown by use of the fluorescent probe DAF-2. This effect was corroborated by the [14C]L-arginine/L-citrulline conversion assay in intact EA.hy926 cells. RWPE (20 hours, 100 to 600 microg/mL) also significantly increased eNOS protein levels up to 2.1-fold. Furthermore, we found an increased human eNOS promotor activity (up to 2-fold) in response to red wine polyphenols (18 hours, 100 to 600 microg/mL), as demonstrated by a luciferase reporter gene assay.

Conclusion: We provide conclusive data showing for the first time that a RWPE increases eNOS expression and subsequent endothelial NO release. Increased active eNOS levels may antagonize the development of endothelial dysfunction and atherosclerosis, a hypothesis that supports the view that red wine indeed may have long-term protective cardiovascular properties mediated by its polyphenols.

MeSH terms

  • Cells, Cultured
  • Citrulline / analysis
  • Citrulline / biosynthesis
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / chemistry
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism*
  • Flavonoids*
  • Gene Expression / drug effects
  • Genes, Reporter
  • Humans
  • Nitric Oxide / analysis
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Synthase / analysis
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type III
  • Phenols / pharmacology*
  • Polymers / pharmacology*
  • Polyphenols
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / physiology
  • Wine*


  • Flavonoids
  • Phenols
  • Polymers
  • Polyphenols
  • Citrulline
  • Nitric Oxide
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III