title: PPAR-γ activation by rosiglitazone suppresses angiotensin II-mediated proliferation and phenotypictransition in cardiac fibroblasts via inhibition of activation of activator protein 1.
abstract: Cardiac fibroblasts play an important role in myocardial remodeling by proliferating, differentiating, and secreting extracellular matrix proteins. Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands have been reported to have a number of cardioprotective properties. However, the mechanism underlying this protective effect has not yet been elucidated. The purpose of the present study was to investigate the effect of rosiglitazone on angiotensin II-induced cardiac fibroblast proliferation and differentiation. Cardiac fibroblasts were stimulated with angiotensin II (10(-7)M) in the presence or absence of rosiglitazone (10(-5)nM). Pretreatment of cardiac fibroblasts with rosiglitazone significantly inhibited angiotensin II-induced cardiac fibroblast proliferation and profibrotic phenotypes differentiation and, thus, reduced the overall production of collagen components. PPAR-γ antagonist GW9662 significantly inhibited these effects of rosiglitazone, suggesting that these effects of rosiglitazone were PPAR-γ-dependent. To investigate the mechanisms involved, we found that PPAR-γ activation by rosiglitazone inhibited the formation of c-fos/c-jun heterodimers and expression of activator protein 1 induced by ANG II and thus inhibited transcription of the downstream genes involved in CFs proliferation and differentiation. Our data suggests PPAR-γ activation could have an anti-fibrotic effect through limiting cardiac fibroblast proliferation and differentiation, which are the critical steps in the pathogenesis of cardiac fibrosis.
authors.affiliation: Department of Cardiology, Provincial Hospital Affiliated to Shandong University, 250020, Jinan, China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Hou
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ying H
authors.initials: YH
authors.lastname: Shen
authors.forename: Tongbao
authors.initials: T
authors.lastname: Liu
authors.forename: Shangming
authors.initials: S
authors.lastname: Song
authors.forename: Lianqun
authors.initials: L
authors.lastname: Cui
authors.forename: Peili
authors.initials: P
authors.lastname: Bu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000235:genetics; D009206:Myocardium / Q000166:cytology*; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism*; D010641:Phenotype; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D047495:PPAR gamma; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D000077154:Rosiglitazone; D000804:Angiotensin II; D019938:Cyclin D1; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Activator protein-1; Cardiac fibroblast; Cyclin D(1); Differentiation; Peroxisome proliferator-activated receptor-γ