title: Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin.
abstract: Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases.
authors.affiliation: From the Department of Cardiology, Renji Hospital (M.C., Z.C., S.C., Z.S., X.W., L.H., L.S., B.H.) and Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences (J.Y.), School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Mingli
authors.initials: M
authors.lastname: Cui
authors.affiliation: From the Department of Cardiology, Renji Hospital (M.C., Z.C., S.C., Z.S., X.W., L.H., L.S., B.H.) and Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences (J.Y.), School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Cai
authors.affiliation: From the Department of Cardiology, Renji Hospital (M.C., Z.C., S.C., Z.S., X.W., L.H., L.S., B.H.) and Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences (J.Y.), School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Shichun
authors.initials: S
authors.lastname: Chu
authors.affiliation: From the Department of Cardiology, Renji Hospital (M.C., Z.C., S.C., Z.S., X.W., L.H., L.S., B.H.) and Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences (J.Y.), School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Sun
authors.affiliation: From the Department of Cardiology, Renji Hospital (M.C., Z.C., S.C., Z.S., X.W., L.H., L.S., B.H.) and Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences (J.Y.), School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Department of Cardiology, Renji Hospital (M.C., Z.C., S.C., Z.S., X.W., L.H., L.S., B.H.) and Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences (J.Y.), School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Liuhua
authors.initials: L
authors.lastname: Hu
authors.affiliation: From the Department of Cardiology, Renji Hospital (M.C., Z.C., S.C., Z.S., X.W., L.H., L.S., B.H.) and Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences (J.Y.), School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yi
authors.affiliation: From the Department of Cardiology, Renji Hospital (M.C., Z.C., S.C., Z.S., X.W., L.H., L.S., B.H.) and Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences (J.Y.), School of Medicine, Shanghai Jiaotong University, Shanghai, China. rjheben@126.com rjshenlinghong@126.com.
authors.forename: Linghong
authors.initials: L
authors.lastname: Shen
authors.affiliation: From the Department of Cardiology, Renji Hospital (M.C., Z.C., S.C., Z.S., X.W., L.H., L.S., B.H.) and Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences (J.Y.), School of Medicine, Shanghai Jiaotong University, Shanghai, China. rjheben@126.com rjshenlinghong@126.com.
authors.forename: Ben
authors.initials: B
authors.lastname: He
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D066253:Vascular Remodeling / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D051176:beta Catenin; D000804:Angiotensin II; D004247:DNA
keywords: angiotensin II; beta catenin; cardiovascular diseases; hypertension; orphan nuclear receptor Nur77; vascular remodeling