Uncoupling of endothelial nitric oxide synthase in cerebral vasculature of Tg2576 mice

Anantha Vijay R Santhanam, Livius V. D'Uscio, Tongrong He, Pritam Das, Steven G Younkin, Zvonimir S Katusic

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

In this study, we tested the hypothesis that reduced bioavailability of tetrahydrobiopterin (BH<inf>4</inf>) is a major mechanism responsible for pathogenesis of endothelial dysfunction in cerebral microvessels of transgenic mice expressing the Swedish double mutation of human amyloid precursor protein (APP) (Tg2576 mice). Endothelial nitric oxide synthase (eNOS) protein expression was significantly increased in cerebral vasculature of Tg2576 mice. In contrast, bioavailability of BH<inf>4</inf> was significantly reduced (p < 0.05). Moreover, superoxide anion production was increased in cerebral microvessels of Tg2576 mice (p < 0.05). Incubation with NOS inhibitor, N<sup>ω</sup>-nitro-L-arginine methyl ester, decreased superoxide anion indicating that uncoupled eNOS is most likely the source of superoxide anion. Increasing BH<inf>4</inf> bioavailability either exogenously by BH<inf>4</inf> supplementation or endogenously by treatment with the selective peroxisome proliferator-activated receptor - delta activator GW501516 (2 mg/kg/day, 14 days) attenuated eNOS uncoupling and decreased superoxide anion production in cerebral microvessels of Tg2576 mice (p < 0.05). Treatment with GW501516 restored the biological activity of endothelial nitric oxide in cerebral microvessels of Tg2576 mice, as indicated by the increased nitrite/nitrate content and 3,5-cyclic guanosine monophosphate levels (p < 0.05). Our studies indicate that sub-optimal BH<inf>4</inf> bioavailability in cerebral vasculature is an important contributor to oxidant stress and endothelial dysfunction in Tg2576 mouse model of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)1129-1138
Number of pages10
JournalJournal of Neurochemistry
Volume134
Issue number6
DOIs
StatePublished - Sep 1 2015

Keywords

  • Alzheimer's disease
  • endothelial dysfunction
  • oxidative stress
  • superoxide anions
  • tetrahydrobiopterin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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