title: NR6A1 couples with cAMP response element binding protein and regulates vascular smooth muscle cell migration.
abstract: Vascular smooth muscle cell (VSMC) migration is implicated in atherosclerosis and restenosis. Nuclear receptor subfamily 6, group A, member 1 (NR6A1) is involved in regulating embryonic stem cell differentiation, reproduction, neuronal differentiation. Functional cooperation between cAMP response element modulator tau (CREMtau) and NR6A1 can direct gene expression in cells. cAMP response element binding protein (CREB) plays a key role in VSMC migration. In this study, we sought to determine whether CREB involved in NR6A1-modulated VSMC migration. VSMCs treated with platelet-derived growth factor-BB (PDGF-BB) displayed reduced mRNA and protein levels of NR6A1. Adenovirus-mediated expression of NR6A1 (Ad-NR6A1) could inhibit PDGF-BB- and serum-induced VSMC migration. The mRNA and protein expressions of secreted phosphoprotein 1 (SPP1) were down-regulated by NR6A1 overexpression. SPP1 promoter reporter activity was repressed by NR6A1. NR6A1 was found to physically couple with nuclear actin and the large subunit of RNA polymerase II. Furthermore, we showed that CREB interacted with NR6A1 in VSMCs. NR6A1 overexpression repressed cAMP response element (CRE) activity. ChIP assay revealed that NR6A1 bind to SPP1 promoter. Luciferase reporter assay showed that NR6A1 regulated SPP1 promoter activity via a putative CRE site. Adenovirus mediated local NR6A1 gene transfer attenuated stenosis after balloon-induced arterial injury in Sprague-Dawley rats. Taken together, this study provided experimental evidence that NR6A1 modulated SPP1 expression via its binding with CREB protein in VSMCs. We also revealed a NR6A1-CREB-SPP1 axis that serves as a regulatory mechanism for atherosclerosis and restenosis.
authors.affiliation: Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yinfang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Hubei University of Medicine, Hubei, China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Cardiovascular Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Zongjun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
authors.affiliation: Institute of Cardiovascular Science, Peking University, Beijing, China.
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.affiliation: Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: zhangnep@hotmail.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001665:Binding Sites; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D015870:Gene Expression; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D058426:Neointima / Q000378:metabolism; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1 / Q000502:physiology*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis / Q000502:physiology; D017207:Rats, Sprague-Dawley
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C539956:Nr6a1 protein, rat; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D020574:Proto-Oncogene Proteins c-sis; C506897:Spp1 protein, rat; D053495:Osteopontin; D000077214:Becaplermin
keywords: CREB; Migration; NR6A1; SPP1; Smooth muscle cell