Yes-associated protein mediates angiotensin II-induced vascular smooth muscle cell phenotypic modulation and hypertensive vascular remodelling
Yes-associated protein mediates angiotensin II-induced vascular smooth muscle cell phenotypic modulation and hypertensive vascular remodelling
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Yes相关蛋白介导血管紧张素II诱导的血管平滑肌细胞表型调节和高血压血管重塑
DOI：
10.1111/cpr.12517
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发表时间：
2018-12-01
影响因子：
8.5
通讯作者：
Wang, Jingfeng
中科院分区：
文献类型：
--
作者：
Lin, Maohuan;Yuan, Woliang;Wang, Jingfeng
目的研究YAP对细胞增殖和分化的调控作用。我们旨在研究YAP在血管紧张素II(Ang II)诱导的高血压血管重构(HVR)和血管平滑肌细胞(VSMCs)表型改变中的作用，并探讨其可能的机制。材料与方法采用血管紧张素转换酶Ⅱ(Ang II)持续输注2周建立高血压大鼠模型。Western blotting、qRT-PCR和共聚焦显微镜检测YAP的表达。构建了YAP-shRNA干扰载体和腺病毒载体。我们使用细胞增殖和迁移分析，伴随着通路抑制剂，以评估生物学功能和潜在的机制。结果Ang II上调YAP在颈动脉中膜的表达，而体内YAP沉默显著减轻HVR，且与血压水平无关。Ang II以剂量和时间依赖的方式上调大鼠VSMC中YAP的表达，促进YAP的核聚集。YAP基因敲除可改善Ang II诱导的VSMCs的表型调节。血管紧张素受体1型拮抗剂氯沙坦或F-肌动蛋白解聚剂Latrunculin B可阻断血管紧张素Ⅱ对YAP的调节，但不能阻断血管紧张素Ⅱ受体拮抗剂PD 123319的作用。用维替泊芬阻断YAP-TEA结构域(TEAD)的相互作用可抑制Ang II诱导的VSMCs的表型调节。结论相关蛋白介导的血管紧张素II诱导VSMCs表型改变和血管重塑。YAP是超越血压控制的HVR的潜在治疗靶点。
Objectives Yes-associated protein (YAP) has been reported to regulate cell proliferation and differentiation. We aimed to characterize the role of YAP in angiotensin II (Ang II)-induced hypertensive vascular remodelling (HVR) and vascular smooth muscle cells (VSMCs) phenotypic modulation and to explore the underlying mechanisms. Materials and methods An HVR rat model was established by continuous Ang II infusion for 2 weeks. Western blotting, qRT-PCR, and confocal microscopy were conducted to assess YAP expression. YAP-shRNA interfering plasmid and adenovirus were constructed to knock down YAP. We used cell proliferation and migration assays, accompanied by pathway inhibitors, to evaluate the biological function and underlying mechanisms. Results Ang II upregulated YAP expression in the media of carotid artery; however, in vivo YAP silencing significantly mitigated HVR, independent of the blood pressure level. Ang II upregulated YAP expression and promoted YAP nuclear accumulation in a dose- and time-dependent manner in rat VSMCs. YAP knockdown ameliorated Ang II-induced VSMCs phenotypic modulation. The regulation of YAP by Ang II could be blocked by pretreatment with angiotensin receptor type 1 antagonist losartan or F-actin depolymerizing agent latrunculin B but not the AT2R antagonist PD 123319. Disrupting the YAP-TEA domain (TEAD) interaction with verteporfin inhibited Ang II-induced VSMCs phenotypic modulation. Conclusions Yes-associated protein mediated angiotensin II-induced VSMCs phenotypic modulation and vascular remodelling. YAP is a potential therapeutic target for HVR beyond blood pressure control.