Grape seed proanthocyanidin extracts enhance endothelial nitric oxide synthase expression through 5'-AMP activated protein kinase/Surtuin 1-Krüpple like factor 2 pathway and modulate blood pressure in ouabain induced hypertensive rats

Biol Pharm Bull. 2012;35(12):2192-7. doi: 10.1248/bpb.b12-00598. Epub 2012 Sep 14.


Grape seed proanthocyanidin extracts (GSPE) belonging to polyphenols, possess various biological effects including anti-inflammation, anti-oxidant, anti-aging, anti-atherosclerosis, etc. GSPE is potential in regulating endothelial function. However, the underlying mechanism is not clear yet. In this study, by small interfering RNA (siRNA) knocking down, we proved that GSPE increase endothelial nitric oxide synthase (eNOS) expression in human umbilical vessel cells (HUVECs) in vitro, which was attributed to its transcription factor Krüpple like factor 2 (KLF2) induction. Furthermore, GSPE activate 5'-AMP activated protein kinase (AMPK) and increase surtuin 1 (SIRT1) protein level, critical for KLF2 induction. We also illuminated the role of GSPE in hypertension treatment. By chronic administration of GSPE in ouabain induced hypertensive rats model, we access the effect of GSPE on blood pressure regulation and the possible mechanisms involved. After 5 weeks feeding, GSPE significantly block the ouabain induced blood pressure increase. The aortic NO production impaired by ouabain was improved. In conclusion, GSPE increase eNOS expression and NO production in an AMPK/SIRT1 dependent manner through KLF2 induction, and attenuate ouabain induced hypertension.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use
  • Aorta / drug effects
  • Aorta / metabolism
  • Blood Pressure / drug effects*
  • Grape Seed Extract / chemistry
  • Grape Seed Extract / pharmacology
  • Grape Seed Extract / therapeutic use*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypertension / chemically induced
  • Hypertension / drug therapy*
  • Hypertension / metabolism
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism*
  • Ouabain
  • Phytotherapy*
  • Proanthocyanidins / pharmacology
  • Proanthocyanidins / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Seeds
  • Sirtuin 1 / metabolism
  • Vitis / chemistry*


  • Antihypertensive Agents
  • Grape Seed Extract
  • Kruppel-Like Transcription Factors
  • Proanthocyanidins
  • Nitric Oxide
  • Ouabain
  • Nitric Oxide Synthase Type III
  • AMP-Activated Protein Kinases
  • SIRT1 protein, human
  • Sirtuin 1