title: Rosiglitazone inhibits angiotensin II-induced CTGF expression in vascular smooth muscle cells - role of PPAR-gamma in vascular fibrosis.
abstract: Angiotensin (Ang) II plays a pivotal role in vascular fibrosis, which leads to serious complications in hypertension and diabetes. Connective tissue growth factor (CTGF) is a potent profibrotic factor implicated in the Ang II-induced pathologic fibrosis process. PPAR-gamma activators thiazolidinediones have been recently reported to have beneficial vascular effects. However, their effects and related molecular mechanisms on extracellular matrix (ECM) turnover in vascular smooth muscle cells (VSMCs) are unknown. The present study evaluated the regulation of Ang II-induced CTGF, ECM production and cell growth by rosiglitazone in VSMCs. In aorta of Ang II-infused rats, CTGF expression was markedly increased, and type III collagen and fibronectin overexpression was observed. Cotreatment with rosiglitazone diminished these changes, whereas increased nuclear PPAR-gamma expression in VSMCs. In growth-arrested VSMCs, rosiglitazone attenuated the proliferation and apoptosis, increased PPAR-gamma production and activation, and reduced CTGF and ECM production in response to Ang II in a dose-dependent fashion. These inhibitory effects were attenuated by the pretreatment of cells with PPAR-gamma antagonist GW9662 or bisphenol A diglycidyl ether (BADGE). Furthermore, rosiglitazone inhibited Ang II-induced Smad2 production and phosphorylation but had no effect on transforming growth factor-beta(1) (TGF-beta(1)) expression. These results suggest that in Ang II-stimulated VSMCs, rosiglitazone caused an antiproliferative, antiapototic effect and reduces ECM production through mechanisms that include reducing CTGF expression, and a crosstalk between PPAR-gamma and Smad may be involved in the inhibitory effects of rosiglitazone. This novel finding suggests a role of PPAR-gamma activators in preventing Ang II-induced vascular fibrosis.
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710004, PR China.
authors.forename: Deng-Feng
authors.initials: DF
authors.lastname: Gao
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Niu
authors.forename: Guang-Hua
authors.initials: GH
authors.lastname: Hao
authors.forename: Ning
authors.initials: N
authors.lastname: Peng
authors.forename: Jin
authors.initials: J
authors.lastname: Wei
authors.forename: Ning
authors.initials: N
authors.lastname: Ning
authors.forename: Nan-Ping
authors.initials: NP
authors.lastname: Wang
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D055513:Connective Tissue Growth Factor; D017931:DNA Primers; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C526316:CCN2 protein, rat; D017931:DNA Primers; D007004:Hypoglycemic Agents; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor