Journal article
Endothelial PPARγ (Peroxisome Proliferator–Activated Receptor-γ) Is Essential for Preventing Endothelial Dysfunction With Aging
Hypertension (Dallas, Tex. 1979), Vol.72(1), pp.227-234
07/01/2018
DOI: 10.1161/HYPERTENSIONAHA.117.10799
PMCID: PMC6002945
PMID: 29735632
Abstract
Little is known about mechanisms that control vascular aging, particularly at the cell-specific level. PPAR gamma (peroxisome proliferator-activated receptor-gamma) exerts protective effects in the vasculature when activated pharmacologically. To gain insight into the cell-specific impact of PPAR gamma, we examined the hypothesis that genetic interference with endothelial PPAR gamma would augment age-induced vascular dysfunction. We studied carotid arteries from adult (11.6 +/- 0.3 months) and old (24.7 +/- 0.6 months) mice with endothelial-specific expression of a human dominant negative mutation in PPAR gamma driven by the vascular cadherin promoter (E-V290M), along with age-matched, nontransgenic littermates. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation in arteries from adult nontransgenic and E-V290M mice and old nontransgenic mice. In contrast, responses to acetylcholine were reduced by >50% in old male and female E-V290M mice (P<0.01). Endothelial function in old E-V290M mice was not altered by an inhibitor of COX (cyclooxygenase) but was restored to normal by a superoxide scavenger, an inhibitor of NADPH oxidase, or inhibition of ROCK (Rho kinase). Relaxation of arteries to nitroprusside, which acts directly on vascular muscle, was similar in all groups. Vascular expression of IL (interleukin)-6, Nox-2, and CDKN2A (a marker of senescence) was significantly increased in old E-V290M mice compared with controls (P<0.05). These findings provide the first evidence that age-related vascular dysfunction, inflammation, and senescence is accelerated after interference with endothelial PPAR gamma via mechanisms involving oxidative stress and ROCK. The finding of an essential protective role for endothelial PPAR gamma has implications for vascular disease and therapy for vascular aging.
Details
- Title: Subtitle
- Endothelial PPARγ (Peroxisome Proliferator–Activated Receptor-γ) Is Essential for Preventing Endothelial Dysfunction With Aging
- Creators
- T. Michael De Silva - La Trobe UniversityYing Li - University of IowaDale A. Kinzenbaw - Karagozian & Case (United States)Curt D. Sigmund - Roy J. and Lucille A. Carver College of MedicineFrank M. Faraci - Veterans Health Administration
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.72(1), pp.227-234
- DOI
- 10.1161/HYPERTENSIONAHA.117.10799
- PMID
- 29735632
- PMCID
- PMC6002945
- NLM abbreviation
- Hypertension
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 8
- Grant note
- Fondation Leducq (Transatlantic Network of Excellence); Leducq Foundation HL-113863; NS-096465; HL-125603; HL-131689 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL131689; R01HL125603; R01HL113863 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 1053786 / National Health and Medical Research Council of Australia; National Health and Medical Research Council (NHMRC) of Australia R01NS096465 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) BX001399 / Department of Veteran's Affair's; US Department of Veterans Affairs I01BX001399 / Veterans Affairs; US Department of Veterans Affairs
- Language
- English
- Date published
- 07/01/2018
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984303857202771
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