Osteoprotegerin promotes intimal hyperplasia and contributes to in-stent restenosis: Role of an αVβ3/FAK dependent YAP pathway
Osteoprotegerin promotes intimal hyperplasia and contributes to in-stent restenosis: Role of an αVβ3/FAK dependent YAP pathway
复制标题
骨保护素促进内膜增生并导致支架内再狭窄：αVβ3/FAK 依赖性 YAP 通路的作用
DOI：
10.1016/j.yjmcc.2020.01.006
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发表时间：
2020-02-01
影响因子：
5
通讯作者：
Zhou, Shenghua
中科院分区：
文献类型：
--
作者：
He, Yuhu;Zou, Pu;Zhou, Shenghua
目的：血管平滑肌细胞（VSMCs）的异常增殖和迁移与经皮冠状动脉介入治疗（PCI）后支架内再狭窄（ISR）有关。骨保护素（OPG）与多种血管疾病有关。然而，OPG对ISR的影响及其机制尚不清楚。我们在这里调查OPG和ISR之间的关联，并证明OPG在新生内膜hyperplasia.Approach和results的作用和潜在机制：从2962例患者接受冠状动脉造影和随访冠状动脉造影在大约一年，291例患者被诊断为ISR，另291例性别和年龄匹配的患者没有ISR被选为对照。ISR患者血清OPG水平显著升高。多因素Logistic回归分析显示OPG水平与ISR风险增加独立相关。在小鼠股动脉钢丝损伤模型中，损伤后血管组织中OPG表达上调。OPG基因缺失对小鼠血管损伤后内膜增生及相关基因表达的影响OPG通过激活Hippo信号通路的下游效应子--yes相关蛋白（雅普），促进人主动脉平滑肌细胞（hASMC）的增殖和迁移，而敲低或抑制hASMC中的雅普可减弱OPG的上述作用。此外，我们发现OPG作为整合素α V β 3的配体，介导了粘着斑激酶（FAK）的磷酸化和肌动蛋白细胞骨架的重组，导致hASMCs中雅普的去磷酸化。OPG依赖性雅普和VSMC的激活可通过α V β 3阻断抗体和FAK和肌动蛋白应力纤维抑制剂的治疗来预防。血清OPG水平升高与PCI后ISR风险增加相关，OPG可通过整合素α V β 3介导的FAK和雅普活化促进损伤后新生内膜增生，提示OPG/雅普抑制可能成为预防PCI术后ISR的一个有吸引力的新靶点。
Objective: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are related to in-stentrestenosis (ISR) following percutaneous coronary intervention (PCI). Osteoprotegerin (OPG) has been implicated in various vascular diseases. However, the effects of OPG on ISR and the underlying mechanism remained elusive. We here investigated the association between OPG and ISR, and to demonstrate the role and potential mechanisms of OPG in neointimal hyperplasia.Approach and results: From 2962 patients who received coronary angiography and follow-up coronary angiography at approximately one year, 291 patients were diagnosed with ISR, and another 291 gender- and agematched patients without ISR were selected as controls. Serum OPG levels were significantly increased in patients with ISR. Multivariable logistic regression analysis indicated that OPG level was independently associated with the increased risk of ISR. In a mouse femoral artery wire injury model, upregulated OPG was evidenced in vascular tissue after injury. OPG deletion attenuated the vascular injury-induced neointimal hyperplasia and related gene expression in mice. OPG promoted neointimal hyperplasia and human aortic smooth muscle cell (hASMC) proliferation and migration through activation of yes-associated protein (YAP), a major downstream effector of the Hippo signaling pathway, whereas knockdown or inhibition of YAP in hASMCs blunted OPGinduced above effects. Moreover, we found that OPG, as a ligand for integrin alpha V beta 3, mediated phosphorylation of focal adhesion kinase (FAK) and actin cytoskeleton reorganization, resulting in YAP dephosphorylation in hASMCs. OPG-dependent YAP and VSMC activation was prevented by treatment with alpha V beta 3-blocking antibodies and inhibitors of FAK and actin stress fibers.Conclusions: Increased serum OPG levels are associated with increased risk of ISR following PCI and OPG could promote neointimal hyperplasia in response to injury through integrin alpha V beta 3 mediated FAK and YAP activation, indicating OPG/YAP inhibition might serve as an attractive novel target for the prevention of ISR after PCI.