title: Activation of PPAR-γ by pioglitazone attenuates oxidative stress in aging rat cerebral arteries through upregulating UCP2.
abstract: Increasing amounts of evidence implicate oxidative stress as having a pivotal role in age-related cerebrovascular dysfunction, which is an important risk factor for the development of cerebrovascular disease. Previous studies have shown that the activation of the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) in vascular endothelial cells results in an improvement of vascular function. Pioglitazone, a well-known PPAR-γ agonist, protects against oxidative stress in the rostral ventrolateral medulla by the upregulation of mitochondrial uncoupling protein 2 (UCP2). In this study, we sought to explore the effects and the underlying mechanisms of pioglitazone on age-related oxidative stress elevation and cerebrovascular dysfunction in aging rat cerebral arteries. A natural aging model was constructed and used in these experiments. One-month oral administration of pioglitazone (20 mg·kg·d) ameliorated the production of reactive oxygen species, promoted endothelial nitric oxide synthase phosphorylation and increased the nitric oxide available, thus improving endothelium-dependent relaxation in aging rat cerebral arteries. One-month pioglitazone administration also restored PPAR-γ expression and increased the levels of UCP2 in aging rat cerebral arteries. Using in vitro studies, we demonstrated that pioglitazone attenuated reactive oxygen species levels in aging human umbilical vein endothelial cells through PPAR-γ activation. Furthermore, we found that this occurs in an UCP2-dependent manner. Our study demonstrated that the activation of PPAR-γ by pioglitazone protected against oxidative stress damage in aging cerebral arteries by upregulating UCP2. PPAR-γ may be a new target in treating age-related cerebrovascular dysfunction.
authors.affiliation: *Department of Cardiology, The First Affiliated Hospital, Chengdu Medical College, Chengdu, China; †Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China; and ‡Department of Pharmacology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
authors.forename: Peijian
authors.initials: P
authors.lastname: Wang
authors.forename: Binghu
authors.initials: B
authors.lastname: Li
authors.forename: Guocai
authors.initials: G
authors.lastname: Cai
authors.forename: Mingqing
authors.initials: M
authors.lastname: Huang
authors.forename: Licheng
authors.initials: L
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: Pu
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Zuo
authors.forename: Qiulin
authors.initials: Q
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000375:Aging; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000071246:Uncoupling Protein 2; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; C000604389:UCP2 protein, human; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D000077205:Pioglitazone