Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction. Physiol Genomics 2016 Feb;48(2):124-34
Date
11/05/2015Pubmed ID
26534936Pubmed Central ID
PMC4729699DOI
10.1152/physiolgenomics.00087.2015Scopus ID
2-s2.0-84961368938 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
The ligand activated nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in the endothelium regulates vascular function and blood pressure (BP). We previously reported that transgenic mice (E-V290M) with selectively targeted endothelial-specific expression of dominant negative PPARγ exhibited endothelial dysfunction when treated with a high-fat diet, and exhibited an augmented pressor response to angiotensin II (ANG II). We hypothesize that interference with endothelial PPARγ would exacerbate ANG II-induced endothelial dysfunction. Endothelial function was examined in E-V290M mice infused with a subpressor dose of ANG II (120 ng·kg(-1)·min(-1)) or saline for 2 wk. ANG II infusion significantly impaired the responses to the endothelium-dependent agonist acetylcholine both in basilar and carotid arteries from E-V290M but not NT mice. This impairment was not due to increased BP, which was not significantly different in ANG II-infused E-V290M compared with NT mice. Superoxide levels, and expression of the pro-oxidant Nox2 gene was elevated, whereas expression of the anti-oxidant genes Catalase and SOD3 decreased in carotid arteries from ANG II-infused E-V290M mice. Increased p65 and decreased Iκ-Bα suggesting increased NF-κB activity was also observed in aorta from ANG II-infused E-V290M mice. The responses to acetylcholine were significantly improved both in basilar and carotid arteries after treatment with Tempol (1 mmol/l), a scavenger of superoxide. These findings provide evidence that interference with endothelial PPARγ accelerates ANG II-mediated endothelial dysfunction both in cerebral and conduit arteries through an oxidative stress-dependent mechanism, suggesting a role for endothelial PPARγ in protecting against ANG II-induced endothelial dysfunction.
Author List
Hu C, Lu KT, Mukohda M, Davis DR, Faraci FM, Sigmund CDAuthor
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetylcholineAngiotensin II
Animals
Antioxidants
Blood Pressure
Carotid Arteries
Catalase
Diet, High-Fat
Endothelium, Vascular
Heart Rate
Ligands
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
NF-kappa B
Oxidative Stress
PPAR gamma
Reactive Oxygen Species
Real-Time Polymerase Chain Reaction
Spectrometry, Fluorescence
Superoxide Dismutase
Superoxides
