Endothelial PPAR gamma (Peroxisome Proliferator-Activated Receptor-gamma) Is Essential for Preventing Endothelial Dysfunction With Aging

摘要

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 (P0.01). 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 (P0.05). 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.