ArticleCardiovascular research2012
Activation of PPARδ prevents endothelial dysfunction induced by overexpression of amyloid-β precursor protein.
Article in Cardiovascular research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 33 citations in OpenAlex.
- Cerebrovascular protective functions of amyloid precursor protein: Progress and therapeutic prospects.Pharmacology & therapeutics · 2025Review
- Expression and function of β-site amyloid precursor protein-cleaving enzyme 2 in vascular endothelium.American journal of physiology. Heart and circulatory physiology · 2025Article
- PPARs in atherosclerosis: The spatial and temporal features from mechanism to druggable targets.Journal of advanced research · 2025Review
- An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases.Journal of clinical and translational hepatology · 2023Review
- Single-cell transcriptomic, transcriptomic, and metabolomic characterization of human atherosclerosis.Annals of translational medicine · 2022Article
- Article
- Tetrahydrobioterin (BH4) Pathway: From Metabolism to Neuropsychiatry.Current neuropharmacology · 2021Review
- PPAR Beta/Delta and the Hallmarks of Cancer.Cells · 2020Review
- Vascular phenotype of amyloid precursor protein-deficient mice.American journal of physiology. Heart and circulatory physiology · 2019Article
- Impairment of amyloid precursor protein alpha-processing in cerebral microvessels of type 1 diabetic mice.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2019Article
- Endothelium-specific amyloid precursor protein deficiency causes endothelial dysfunction in cerebral arteries.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2018Article
- Pulsatile stretch as a novel modulator of amyloid precursor protein processing and associated inflammatory markers in human cerebral endothelial cells.Scientific reports · 2018Article
- Atherosclerosis is exacerbated by chitinase-3-like-1 in amyloid precursor protein transgenic mice.Theranostics · 2018Article
- Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2017Article
- Expression and Processing of Amyloid Precursor Protein in Vascular Endothelium.Physiology (Bethesda, Md.) · 2017Review
- Apolipoprotein E and Sex Bias in Cerebrovascular Aging of Men and Mice.Trends in neurosciences · 2016Review
- Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice.Gene therapy · 2016Article
- Uncoupling of endothelial nitric oxide synthase in cerebral vasculature of Tg2576 mice.Journal of neurochemistry · 2015Article
- Differences Between Tg2576 and Wild Type Mice in the NMDA Receptor-Nitric Oxide Pathway After Prolonged Application of a Diet High in Advanced Glycation End Products.Neurochemical research · 2015Article
- Pan-PPAR modulation effectively protects APP/PS1 mice from amyloid deposition and cognitive deficits.Molecular neurobiology · 2015Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
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 Ser(1177) in aortas. HPLC analysis revealed that tetrahydrobiopterin (BH(4)) levels were reduced in Tg2576 mice aortas. This was caused by increased oxidation of BH(4) 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 BH(4) 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.
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Registered trials
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