title: High Mobility Group Box 1 Mediates Interferon-γ-Induced Phenotypic Modulation of Vascular Smooth Muscle Cells.
abstract: The phenotypic modulation of VSMCs is a key cellular event driving neointimal formation and vascular remodeling. As a multifaceted cytokine of cell-mediated immunity, IFN-γ has been shown to play a critical role in the pathogenesis of vascular proliferative diseases. Although the important function of IFN-γ on regulating VSMC activation is well established, the molecular mechanisms by which elicits VSMC responses are poorly defined. Recent studies have identified HMGB1 as a principal effector to mediate IFN-γ-dependent biological functions in multiple cell types. Moreover, SIRT1 has emerged as a critical regulator of cellular processes through deacetylating multiple substrates, including HMGB1. Thus, we examined the role of IFN-γ on HMGB1 release, SIRT1 expression, and VSMC phenotypic modulation as well as the underlying molecular mechanisms. We show that IFN-γ dose-dependently induces HMGB1 cytoplasmic accumulation and its active release from VSMCs, resulting in enhanced HMGB1 in the medium. Conversely, IFN-γ treatment led to a dramatic decrease in SIRT1 expression. Additionally, pretreatment with resveratrol, a selective SIRT1 activator, abrogated IFN-γ-induced HMGB1 translocation and its release. Moreover, IFN-γ stimulates VSMC phenotypic modulation to an activated synthetic state characterized by the repression of SMC differentiation markers such as SM22α and calponin and the increase in cell motility. In contrast, blocking HMGB1 release or activity by resveratrol and HMGB1-neutralizing antibody prevents IFN-γ-induced phenotypic modulation of VSMCs. Overall, this study provides the first evidence showing that HMGB1 plays a critical role in regulating VSMC phenotypic modulation, suggesting that HMGB1 may be a potential therapeutic target to prevent vascular occlusive diseases. J. Cell. Biochem. 118: 518-529, 2017. © 2016 Wiley Periodicals, Inc.
authors: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Kun
authors: K
authors: Wang
authors: Department of Gerontology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Wei
authors: W
authors: Li
authors: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Qihong
authors: Q
authors: Yu
authors: Aab Cardiovascular Research Institute, University of Rochester, School of Medicine and Dentistry, Rochester, New York.
authors: Bing
authors: B
authors: Guo
authors: Second Department of Hepatobiliary Surgery, Zhujiang Hospital, State Key Laboratory of Organ Failure Research, Co-Innovation Center for Organ Failure Research, Southern Medical University, Guangzhou, China.
authors: Bin
authors: B
authors: Yang
authors: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Chen
authors: C
authors: Zhang
authors: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Min
authors: M
authors: Li
authors: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Jinjin
authors: J
authors: Li
authors: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Shaobo
authors: S
authors: Hu
authors: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Qichang
authors: Q
authors: Zheng
authors: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Zifang
authors: Z
authors: Song
mesh_terms: D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D013267:Stilbenes; D007371:Interferon-gamma; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: HIGH MOBILITY GROUP BOX 1; INTERFERON-γ; PHENOTYPE; SIRTUIN-1; VASCULAR SMOOTH MUSCLE CELLS