PPARδ agonist GW501516 prevents uncoupling of endothelial nitric oxide synthase in cerebral microvessels of hph-1 mice

Brain Res. 2012 Nov 5;1483:89-95. doi: 10.1016/j.brainres.2012.09.012. Epub 2012 Sep 13.

Abstract

Peroxisome proliferator-activated receptor delta (PPARδ) is ubiquitously expressed in the vasculature, including cerebral circulation. The role of PPARδ in metabolism of tetrahydrobiopterin (BH₄) has not been studied in the cerebral microvasculature. In the present study, the effects of PPARδ agonist GW501516 on uncoupling of endothelial nitric oxide synthase (eNOS) were determined in cerebral microvessels of BH₄-deficient hph-1 mice. Wild-type (B6CBA) and hph-1 mice were orally gavaged with a selective PPARδ activator, GW501516 (2 mg/kg/day) for 14 days, and thereafter, cerebral microvessels were isolated and studied. Treatment of hph-1 mice with GW501516 significantly reduced oxidation of BH₄ and increased the ratio of BH₄ to 7,8-BH₂ (P<0.05, n=6-9). Attenuation of L-NAME-inhibitable superoxide anion levels by GW501516 demonstrated that activation of PPARδ might prevent uncoupling of endothelial nitric oxide synthase (eNOS, P<0.05, n=6-9). Western blotting studies demonstrated that GW501516 selectively increased the endothelial expressions of CuZn superoxide dismutase (P<0.05, n=6-9) and catalase (P<0.05, n=6-8). PPARδ activation increased the total nitrite and nitrate (NO₂+NO₃) content in cerebral microvessels (P<0.05, n=6). Obtained results suggest that in vivo activation of PPARδ prevents eNOS uncoupling, restores bioavailability of NO and may help preserve endothelial function in the BH₄-deficient cerebral circulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Biopterin / analogs & derivatives
  • Biopterin / metabolism
  • Blood Pressure / drug effects
  • Cerebral Cortex / anatomy & histology
  • Enzyme Inhibitors / pharmacology
  • GTP Cyclohydrolase / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • In Vitro Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Microvessels / cytology
  • Microvessels / drug effects*
  • Microvessels / enzymology*
  • Mutation / genetics
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide Synthase Type III / metabolism*
  • PPAR delta / antagonists & inhibitors
  • Polycomb Repressive Complex 1 / genetics*
  • Superoxides / metabolism
  • Thiazoles / pharmacology*

Substances

  • Enzyme Inhibitors
  • GW 501516
  • PPAR delta
  • Phc1 protein, mouse
  • Thiazoles
  • Superoxides
  • Biopterin
  • Nitric Oxide Synthase Type III
  • Polycomb Repressive Complex 1
  • GTP Cyclohydrolase
  • sapropterin
  • NG-Nitroarginine Methyl Ester