High Mobility Group Box 1 Mediates Interferon--Induced Phenotypic Modulation of Vascular Smooth Muscle Cells
High Mobility Group Box 1 Mediates Interferon--Induced Phenotypic Modulation of Vascular Smooth Muscle Cells
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高迁移率组盒 1 介导干扰素诱导的血管平滑肌细胞表型调节
DOI：
10.1002/jcb.25682
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发表时间：
2017-03-01
影响因子：
4
通讯作者：
Song, Zifang
中科院分区：
文献类型：
--
作者：
Wang, Kun;Li, Wei;Song, Zifang
VSMC 的表型调节是驱动新内膜形成和血管重塑的关键细胞事件。作为细胞介导免疫的多方面细胞因子，IFN-已被证明在血管增殖性疾病的发病机制中发挥着关键作用。尽管 IFN-α 在调节 VSMC 激活方面的重要功能已得到充分证实，但引发 VSMC 反应的分子机制尚不清楚。最近的研究已确定 HMGB1 是介导多种细胞类型中 IFN 依赖性生物功能的主要效应器。此外，SIRT1 通过使多种底物（包括 HMGB1）脱乙酰化，已成为细胞过程的关键调节剂。因此，我们研究了 IFN-α 对 HMGB1 释放、SIRT1 表达和 VSMC 表型调节的作用以及潜在的分子机制。我们发现，IFN-剂量依赖性地诱导 HMGB1 细胞质积累及其从 VSMC 中主动释放，从而导致培养基中 HMGB1 增强。相反，IFN-治疗导致SIRT1表达急剧下降。此外，用白藜芦醇（一种选择性 SIRT1 激活剂）进行预处理，可消除 IFN 诱导的 HMGB1 易位及其释放。此外，IFN-刺激 VSMC 表型调节至激活的合成状态，其特征是抑制 SMC 分化标记物（例如 SM22 和钙调蛋白）以及细胞运动性的增加。相反，通过白藜芦醇和 HMGB1 中和抗体阻断 HMGB1 释放或活性可防止 IFN 诱导的 VSMC 表型调节。总的来说，这项研究提供了第一个证据表明HMGB1在调节VSMC表型调节中发挥着关键作用，表明HMGB1可能是预防血管闭塞性疾病的潜在治疗靶点。 J.细胞。生物化学。 118：518-529，2017 年。(c) 2016 年 Wiley 期刊公司。
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- has been shown to play a critical role in the pathogenesis of vascular proliferative diseases. Although the important function of IFN- 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--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- on HMGB1 release, SIRT1 expression, and VSMC phenotypic modulation as well as the underlying molecular mechanisms. We show that IFN- dose-dependently induces HMGB1 cytoplasmic accumulation and its active release from VSMCs, resulting in enhanced HMGB1 in the medium. Conversely, IFN- treatment led to a dramatic decrease in SIRT1 expression. Additionally, pretreatment with resveratrol, a selective SIRT1 activator, abrogated IFN--induced HMGB1 translocation and its release. Moreover, IFN- stimulates VSMC phenotypic modulation to an activated synthetic state characterized by the repression of SMC differentiation markers such as SM22 and calponin and the increase in cell motility. In contrast, blocking HMGB1 release or activity by resveratrol and HMGB1-neutralizing antibody prevents IFN--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. (c) 2016 Wiley Periodicals, Inc.