title: Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta.
abstract: Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes.
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China; Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Rui-Qing
authors.initials: RQ
authors.lastname: He
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China; Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China; Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Bao-Li
authors.initials: BL
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China; Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China; Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Mo-Na
authors.initials: MN
authors.lastname: Hong
authors.affiliation: Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Qi-Zhi
authors.initials: QZ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China; Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Shanghai Institute of Hypertension, Shanghai, China. Electronic address: whan020@gmail.com.
authors.forename: Wei-Qing
authors.initials: WQ
authors.lastname: Han
authors.affiliation: State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China; Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Shanghai Institute of Hypertension, Shanghai, China. Electronic address: gaopingjin@sibs.ac.cn.
authors.forename: Ping-Jin
authors.initials: PJ
authors.lastname: Gao
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D000804:Angiotensin II; D010975:Platelet Aggregation Inhibitors
keywords: Adventitial fibroblast; Adventitial remodeling; Angiotensin II; Protease-activated receptor