title: Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation.
abstract: Nur77 is an orphan nuclear receptor that belongs to the nuclear receptor 4A (NR4A) subfamily, which has been implicated in a variety of biological events, such as cell apoptosis, proliferation, inflammation, and metabolism. Activation of Nur77 has recently been shown to be beneficial for the treatment of cardiovascular and metabolic diseases. The purpose of this study is to identify novel natural Nur77 activators and investigate their roles in preventing vascular diseases. By measuring Nur77 expression using quantitative RT-PCR, we screened active ingredients extracted from Chinese herb medicines with beneficial cardiovascular effects. Hyperoside (quercetin 3-D-galactoside) was identified as one of the potent activators for inducing Nur77 expression and activating its transcriptional activity in vascular smooth muscle cells (VSMCs). We demonstrated that hyperoside, in a time and dose dependent manner, markedly increased the expression of Nur77 in rat VSMCs, with an EC50 of ∼0.83 μM. Mechanistically, we found that hyperoside significantly increased the phosphorylation of ERK1/2 MAP kinase and its downstream target cAMP response element-binding protein (CREB), both of which contributed to the hyperoside-induced Nur77 expression in rat VSMCs. Moreover, through activation of Nur77 receptor, hyperoside markedly inhibited both vascular smooth muscle cell proliferation in vitro and the carotid artery ligation-induced neointimal formation in vivo. These findings demonstrate that hyperoside is a potent natural activator of Nur77 receptor, which can be potentially used for prevention and treatment of occlusive vascular diseases.
authors.affiliation: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Room 368G, Philadelphia 19107, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Room 368G, Philadelphia 19107, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yi
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Room 368G, Philadelphia 19107, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Room 368G, Philadelphia 19107, USA.
authors.forename: Nadan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Pengguo
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China. Electronic address: gboss@126.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Guo
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Room 368G, Philadelphia 19107, USA. Electronic address: jianxin.sun@jefferson.edu.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D017931:DNA Primers; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000187:drug effects*
chemical_list: D017931:DNA Primers; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; C021304:hyperoside; D011794:Quercetin
keywords: Hyperoside; Neointimal formation; Nur77; Proliferation; Vascular smooth muscle cells