title: Inhibition of estrogen related receptor α attenuates vascular smooth muscle cell proliferation and migration by regulating RhoA/p27Kip1and β-Catenin/Wnt4 signaling pathway.
abstract: RhoA/p27Kip1and β-Catenin/Wnt4 signaling processes play central roles in proliferation and migration in vascular smooth muscle cells (VSMCs). ERRα, a member of orphan nuclear receptors, is a potent prognostic factor in breast, ovarian, colon and other types of tumors. However, biological significance of ERRα in VSMCs as well as the molecular mechanisms remains largely unknown. Therefore, the present study was designed to investigate whether ERRα is involved in the proliferation and migration of VSMCs in vitro and neointimal formation in vivo. The specific ERRα inverse agonist XCT790 (or ERRα shRNA) resulted in a significant inhibition of proliferation and phenotypic switch in cultured rat aortic SMCs (RASMCs). Furthermore, cycle progression, cell cycle protein transcription as well as hyperphosphorylation of the retinoblastoma protein (Rb) in RASMCs were prevented by downregulation of ERRα. Transwell assay demonstrated that migratory capacity of RASMCs was also inhibited the treatment of XCT790 (or ERRα shRNA). At the molecular levels, RhoA/p27Kip1and β-Catenin/Wnt4 signaling pathways are involved in ERRα-mediated RASMCs growth and migration. Finally, inhibition of ERRα significantly attenuated neointimal formation in rat artery after balloon injury. These results help to further understand vascular remodeling and suggest that ERRα might be a potential target for the treatment of vascular proliferative diseases.
authors.affiliation: Department of Pharmacy, Huashan Hospital North, Fudan University, Shanghai 201907, China. Electronic address: qyli1234@163.com.
authors.forename: Qunyi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of General Surgery, Huashan Hospital North, Fudan University, Shanghai 201907, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pharmacy, Huashan Hospital North, Fudan University, Shanghai 201907, China.
authors.forename: Liudi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Huashan Hospital North, Fudan University, Shanghai 201907, China.
authors.forename: Haifei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology, Huashan Hospital North, Fudan University, Shanghai 201907, China.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, Jinan 250353, China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmacy, Jinshan Branch of the Sixth People's Hospital, Affiliated with Shanghai Jiaotong University, Shanghai 201500, China.
authors.forename: Wanxian
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Pharmacy, Huashan Hospital North, Fudan University, Shanghai 201907, China; Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Mingkang
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Department of Pharmacy, Huashan Hospital North, Fudan University, Shanghai 201907, China. Electronic address: xiaojin_shi@hotmail.com.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Shi
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D058426:Neointima / Q000188:drug therapy; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D060528:Wnt4 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D009570:Nitriles; D011960:Receptors, Estrogen; D013844:Thiazoles; D060528:Wnt4 Protein; D051176:beta Catenin; D020742:rhoA GTP-Binding Protein; D000097983:ERRalpha Estrogen-Related Receptor; C555583:Wnt4 protein, rat; C488234:XCT790
keywords: Estrogen related receptor α; Migration; Neointimal formation; Proliferation; Restenosis; Vascular smooth muscle cells