Peroxisome proliferator-activated receptor-γ protects against vascular aging

Abstract

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-γ (PPARγ) may play a protective role in the vasculature, but the potential importance of PPARγ in vascular aging is unknown. To examine the hypothesis that PPARγ normally protects against vascular aging, we studied heterozygous knockin mice expressing a human dominant-negative mutation in PPARγ (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 ∼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 PPARγ function accelerates vascular aging, suggesting a novel role for PPARγ in protecting against age-induced oxidative stress and endothelial dysfunction.

Fig. 1.

Responses of carotid arteries to submaximal concentrations of acetylcholine (left) and nitroprusside (right) in adult and old wild-type (WT) and PPARγ L/+ mice. All data are expressed as means ± SE; n = 7–10 in each group.

Fig. 2.

Maximum responses of carotid arteries to acetylcholine (10–4 M) (top) and nitroprusside (10–4 M) (bottom) in adult and old wild-type (WT) and PPARγ L/+ mice. All data are expressed as means ± SE; n = 7–10 in each group.

Fig. 3.

Contraction of carotid arteries to U46619 and endothelin-1 in adult and old WT and L/+ mice. *P < 0.05 vs. adult of the same genotype; n = 7–10 in each group.

Fig. 4.

Relative expression levels of mRNA in aorta from adult and old wild-type (WT) and PPARγ L/+ mice. Expression of Nox2 was increased significantly in old L/+ mice compared with adult WT (*P < 0.05 vs. adult and old WT, as well as adult L/+). Expression of AT1 receptors (AT1-R) tended to increase in old L/+ mice (0.05 < P <0.1 vs. WT). n = 7–10 in each group.