Endothelial PPARγ (Peroxisome Proliferator-Activated Receptor-γ) Is Essential for Preventing Endothelial Dysfunction With Aging. Hypertension 2018 Jul;72(1):227-234
Date
05/08/2018Pubmed ID
29735632Pubmed Central ID
PMC6002945DOI
10.1161/HYPERTENSIONAHA.117.10799Scopus ID
2-s2.0-85053758174 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
Little is known about mechanisms that control vascular aging, particularly at the cell-specific level. PPARγ (peroxisome proliferator-activated receptor-γ) exerts protective effects in the vasculature when activated pharmacologically. To gain insight into the cell-specific impact of PPARγ, we examined the hypothesis that genetic interference with endothelial PPARγ 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 PPARγ 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 PPARγ via mechanisms involving oxidative stress and ROCK. The finding of an essential protective role for endothelial PPARγ has implications for vascular disease and therapy for vascular aging.
Author List
De Silva TM, Li Y, Kinzenbaw DA, Sigmund CD, Faraci FMAuthor
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgingAnimals
Carotid Arteries
Disease Models, Animal
Endothelium, Vascular
Female
Gene Expression Regulation
Male
Mice
Mice, Inbred C57BL
Oxidative Stress
PPAR gamma
RNA
Vascular Diseases
Vasodilation
