Peroxisome proliferator-activated receptor-γ protects against vascular aging

Modrick ML, Kinzenbaw DA, Chu Y, Sigmund CD, Faraci FM. Peroxisome proliferator-activated receptor-gamma protects against vascular aging. Am J Physiol Regul Integr Comp Physiol 302: R1184-R1190, 2012. First published March 28, 2012; doi:10.1152/ajpregu.00557.2011.-Vascular disease occurs commonly during aging. Carotid artery and cerebrovascular disease are major causes of stroke and contributors to dementia. Recent evidence suggests that peroxisome proliferator-activated receptor-gamma (PPAR gamma) may play a protective role in the vasculature, but the potential importance of PPAR gamma in vascular aging is unknown. To examine the hypothesis that PPAR gamma normally protects against vascular aging, we studied heterozygous knockin mice expressing a human dominant-negative mutation in PPAR gamma (P465L, designated L/+). Endothelial dysfunction, a major contributor to vascular disease, was studied using carotid arteries from adult (8 +/- 1 mo) and old (24 +/- 1 mo) L/+ mice and wild-type littermates. In arteries from wild-type mice, responses to the endothelium-dependent agonist ACh were similar in adult and old wild-type mice but were reduced by similar to 50% in old L/+ mice (n = 7-10, P < 0.05). Impaired responses in arteries from old L/+ mice were restored to normal by a scavenger of superoxide. Relaxation of arteries to nitroprusside (an NO donor) was similar in all groups. Contraction of arteries to U46619 was not affected by age or genotype, while maximal responses to endothelin-1 were reduced with age in both wild-type and L/+ mice. Vascular expression (mRNA) of the catalytic component of NADPH oxidase (Nox2) was not altered in wild-type mice but was increased significantly in old L/+ mice. These findings provide the first evidence that interference with PPAR gamma function accelerates vascular aging, suggesting a novel role for PPAR gamma in protecting against age-induced oxidative stress and endothelial dysfunction.