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

Anantha Vijay R Santhanam, Livius V. D'uscio, Tongrong He, Zvonimir S Katusic

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 BH 4-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 (NO2NO3) 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.

Original languageEnglish (US)
Pages (from-to)89-95
Number of pages7
JournalBrain Research
Volume1483
DOIs
StatePublished - Nov 5 2012

Fingerprint

PPAR delta
Nitric Oxide Synthase Type III
Microvessels
Cerebrovascular Circulation
NG-Nitroarginine Methyl Ester
Nitrites
GW 501516
Superoxides
Nitrates
Catalase
Biological Availability
Superoxide Dismutase
Western Blotting

Keywords

  • Antioxidant
  • Cerebral microvessel
  • eNOS uncoupling
  • GTP cyclohydrolase I
  • Nitric oxide

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

PPARδ agonist GW501516 prevents uncoupling of endothelial nitric oxide synthase in cerebral microvessels of hph-1 mice. / Santhanam, Anantha Vijay R; D'uscio, Livius V.; He, Tongrong; Katusic, Zvonimir S.

In: Brain Research, Vol. 1483, 05.11.2012, p. 89-95.

Research output: Contribution to journalArticle

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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 BH 4-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 (NO2NO3) 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.",
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AU - Katusic, Zvonimir S

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AB - 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 BH 4-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 (NO2NO3) 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.

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