Peroxisome proliferator-activated receptor-gamma agonists attenuate angiotensin II-induced collagen type I expression in adventitial fibroblasts.
1. Angiotensin (Ang) II-mediated oxidative stress may be important in enhanced adventitial fibroblast collagen formation. The aim of the present study was to test whether PPAR-gamma agonists 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ2) and pioglitazone could alter AngII-induced collagen type I formation in vascular adventitial fibroblasts via reactive oxygen species (ROS). 2. Vascular adventitial fibroblasts were isolated from rat thoracic aortas of male Sprague-Dawley rats and treated with different concentrations of AngII for different periods of time. The expression of collagen type I induced by AngII was examined by western blot. Expression of PPAR-gamma mRNA was examined by reverse transcription-polymerase chain reaction (RT-PCR). Intracellular ROS generation was measured by flow cytometry. Activation of transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 was assessed by an electrophoretic mobility shift assay. 3. Angiotensin II increased expression of collagen type I in a time- and dose-dependent manner in adventitial fibroblasts. In addition, AngII stimulated intracellular generation of ROS in adventitial fibroblasts. Pretreatment of cells with 15d-PGJ2 and pioglitazone attenuated collagen type I expression and generation of ROS induced by AngII, respectively. Moreover, we observed that N-acetylcysteine inhibited collagen type I expression induced by AngII as did the PPAR-gamma agonists. Angiotensin II treatment activated the redox-sensitive transcription factors NF-kappaB and AP-1, whereas pretreatment with 15d-PGJ2 and pioglitazone reduced the AngII-induced DNA-binding activity of NF-kappaB but not AP-1. 4 Our data demonstrate that the PPAR-gamma agonists 15d-PGJ2 and pioglitazone attenuate AngII-mediated collagen type I expression in adventitial fibroblasts, which may be mediated by the modulation of ROS release and the redox-sensitive transcription factor NF-kappaB.
Shanghai Key Laboratory of Vascular Biology at Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai, China.
Jia
J
Zhang
Ning-Yuan
NY
Fang
Ping-Jin
PJ
Gao
Ling-Yun
LY
Wu
Wei-Qing
WQ
Han
Shu-Jie
SJ
Guo
Wei-Li
WL
Shen
Ding-Liang
DL
Zhu
D000111:Acetylcysteine / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D003238:Connective Tissue / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D024042:Collagen Type I; D016166:Free Radical Scavengers; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D015230:Prostaglandin D2; D000111:Acetylcysteine; D000077205:Pioglitazone