Beneficial effect of the oligomerized polyphenol oligonol on high glucose-induced changes in eNOS phosphorylation and dephosphorylation in endothelial cells

Br J Pharmacol. 2010 Feb;159(4):928-38. doi: 10.1111/j.1476-5381.2009.00594.x. Epub 2010 Jan 29.

Abstract

Background and purpose: Hyperglycaemia is known to reduce nitric oxide (NO) bioavailability by modulating endothelial NO synthase (eNOS) activity, and polyphenols are believed to have cardiovascular benefit. One possible mechanism could be through interaction with eNOS.

Experimental approach: The effects of the oligomerized polyphenol oligonol on eNOS phosphorylation status and activity were examined in porcine aortic endothelial cells cultured in high glucose concentrations.

Key results: Exposure to high glucose concentrations strongly inhibited eNOS phosphorylation at Ser-1177 and dephosphorylation at Thr-495 in bradykinin (BK)-stimulated cells. These inhibitory effects of high glucose were significantly prevented by treatment with oligonol. Akt and p38 mitogen-activated protein kinase (MAPK) were activated in BK-stimulated cells. High glucose inhibited Akt activation but enhanced p38 MAPK activation, both of which were reversed by oligonol treatment. The phosphatidylinositol 3-kinase inhibitor wortmannin blocked the reversal by oligonol of phosphorylation at Ser-1177, but not dephosphorylation at Thr-495, in BK-stimulated cells exposed to high glucose. The effect of oligonol on BK dephosphorylation under high glucose was mimicked by protein kinase C (PKC) epsilon-neutralizing peptides. These data suggest that the effects of oligonol on high glucose-induced attenuation of eNOS Ser-1177 phosphorylation and Thr-495 dephosphorylation may be regulated by Akt activation and PKCepsilon inhibition respectively. Oligonol also prevented high glucose-induced attenuation of BK-stimulated NO production.

Conclusions and implications: Oligonol prevented the impairment of eNOS activity induced by high glucose through reversing altered eNOS phosphorylation status. This mechanism may underlie the beneficial cardiovascular health effects of this oligomerized polyphenol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bradykinin / metabolism
  • Cardiovascular Agents / pharmacology*
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Glucose / metabolism*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type III / metabolism*
  • Phenols / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Kinase C-epsilon / metabolism
  • Protein Processing, Post-Translational / drug effects*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Serine
  • Signal Transduction / drug effects
  • Superoxide Dismutase / metabolism
  • Swine
  • Threonine
  • Time Factors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cardiovascular Agents
  • Phenols
  • Reactive Oxygen Species
  • oligonol
  • Threonine
  • Nitric Oxide
  • Serine
  • Catechin
  • Nitric Oxide Synthase Type III
  • Superoxide Dismutase
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C-epsilon
  • p38 Mitogen-Activated Protein Kinases
  • Glucose
  • Bradykinin