Abstract
Abstract 76: Genetic Interference with PPARγ in Endothelium Accelerates Oxidative Stress, Inflammation, and Vascular Senescence With Aging
Stroke (1970), Vol.46(suppl_1), p.A76
02/2015
DOI: 10.1161/str.46.suppl_1.76
Abstract
Although aging is the greatest risk factor for vascular disease and stroke, very little is known regarding mechanisms that control vascular aging. Endothelial dysfunction - a critical element of carotid artery and cerebrovascular disease - progresses with age, contributing to increased risk for ischemic stroke and cognitive impairment. The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) exerts protective effects in the vasculature when pharmacologically activated. Because endothelial PPARγ may normally protect against vascular disease, we examined the hypothesis that genetic interference with PPARγ in endothelium would promote vascular aging. We studied carotid arteries from adult (11-12 mo) and old (24±1 mo) transgenic mice with endothelial specific expression of a dominant negative mutation in PPARγ driven by the vascular cadherin promoter (designated E-V290M), along with age-matched, non-transgenic (NT) littermates. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of arteries from adult NT and E-V290M mice as well as old NT mice. In contrast, responses to acetylcholine were reduced by greater than 50% in old E-V290M mice (P<0.01). Endothelial function in old E-V290M mice was not altered by an inhibitor of cyclooxygenase, but was restored to normal by a superoxide scavenger, or an inhibitor of NADPH oxidase, or inhibition of Rho kinase. Relaxation of arteries to nitroprusside, which acts directly on vascular muscle, was similar in all groups. Vascular expression of interleukin-6, a mediator of vascular disease, was increased 1.6-fold in old NT mice, but almost 9-fold in old E-V290M mice (P<0.05). Interestingly, expression of CDKN2A, a molecular marker of senescence, was increased 2.6-fold in old NT mice, but almost 6-fold in old E-V290M mice (P<0.05). These findings provide the first evidence that senescence and age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARγ through mechanisms that appear to involve oxidative stress, inflammation, and Rho kinase. This critical role for endothelial PPARγ has implications for vascular pathophysiology as well as therapeutic approaches for age-induced large and small vessel disease.
Details
- Title: Subtitle
- Abstract 76: Genetic Interference with PPARγ in Endothelium Accelerates Oxidative Stress, Inflammation, and Vascular Senescence With Aging
- Creators
- Ying Li - University of IowaTravice M De Silva - University of IowaDale A Kinzenbaw - University of IowaCurt D Sigmund - University of IowaFrank M Faraci - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Stroke (1970), Vol.46(suppl_1), p.A76
- DOI
- 10.1161/str.46.suppl_1.76
- ISSN
- 0039-2499
- eISSN
- 1524-4628
- Language
- English
- Date published
- 02/2015
- Academic Unit
- Molecular Physiology and Biophysics; Neuroscience and Pharmacology; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984303994902771
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