Activation of PPARδ prevents endothelial dysfunction induced by overexpression of amyloid-β precursor protein

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

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

AimsExisting evidence suggests that amyloid-β precursor protein (APP) causes endothelial dysfunction and contributes to pathogenesis of atherosclerosis. In the present study, experiments were designed to: (1) determine the mechanisms underlying endothelial dysfunction and (2) define the effects of peroxisome proliferator-activated receptor delta (PPARδ) ligand on endothelial function in transgenic Tg2576 mice overexpressing mutated human APP.Methods and resultsConfocal microscopy and western blot analyses of wild-type mice aortas provided evidence that APP protein is mainly present in endothelial cells. Overexpression of APP significantly impaired endothelium-dependent relaxations to acetylcholine and phosphorylation of endothelial nitric oxide synthase at Ser1177 in aortas. HPLC analysis revealed that tetrahydrobiopterin (BH4) levels were reduced in Tg2576 mice aortas. This was caused by increased oxidation of BH4 and reduced expression and activity of GTP-cyclohydrolase I. Furthermore, gp91phox protein expression and superoxide anion production were increased in aortas of Tg2576 mice. This augmented superoxide formation was completely prevented by the NADPH oxidase inhibitor VAS2870. Expression of copper-/zinc-superoxide dismutase (Cu/ZnSOD) and extracellular SOD was downregulated. Treatment with PPARδ ligand GW501516 (2 mg/kg/day) for 14 days significantly increased BH4 bioavailability and improved endothelium-dependent relaxations in Tg2576 mice aortas. GW501516 also normalized protein expression of gp91 phox and SODs, thereby reducing production of superoxide anion in the aortas.ConclusionOur results suggest that in APP transgenic mice loss of nitric oxide and increased oxidative stress are the major causes of endothelial dysfunction. The vascular protective effects of GW501516 in Tg2576 mice appear to be critically dependent on prevention of superoxide anion production.

Original languageEnglish (US)
Pages (from-to)504-512
Number of pages9
JournalCardiovascular research
Volume96
Issue number3
DOIs
StatePublished - Dec 1 2012

Keywords

  • Amyloid-β precursor protein
  • Atherosclerosis
  • Endothelial function
  • Superoxide anion
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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