Arterial Wall Stress Induces Phenotypic Switching of Arterial Smooth Muscle Cells in Vascular Remodeling by Activating the YAP/TAZ Signaling Pathway
Arterial Wall Stress Induces Phenotypic Switching of Arterial Smooth Muscle Cells in Vascular Remodeling by Activating the YAP/TAZ Signaling Pathway
复制标题
动脉壁应力通过激活 YAP/TAZ 信号通路诱导血管重塑中动脉平滑肌细胞的表型转换
DOI：
10.1159/000495376
复制
发表时间：
2018-01-01
影响因子：
--
通讯作者：
Liu, Jingjin
中科院分区：
文献类型：
--
作者：
Wang, Yongshun;Cao, Wei;Liu, Jingjin
背景/目的：动脉壁应力或生物力学拉伸的增加影响动脉粥样硬化病变的发生。该起始由Yes相关蛋白（雅普）和具有PDZ结合基序的转录共激活因子（TAZ）介导，它们都是Hippo通路的效应子。在这项研究中，雅普/TAZ蛋白在调节牵张介导的人脐动脉平滑肌细胞（HUASMCs）的增殖表型的功能作用进行了检查。方法：将HUASMCs接种在Matrigel涂层的硅胶室上，生长48 h后进行生物力学拉伸24 h。用雅普/TAZ小干扰RNA特异性地敲低HUASMCs中雅普/ TAZ的表达。结果如下：我们观察到，通过生物力学拉伸激活雅普/TAZ参与调节HUASMC表型转换的关键方面。雅普/TAZ敲低显著减弱了牵张诱导的HUASMCs增殖和促炎表型。此外，阿托伐他汀（一种抗动脉粥样硬化药物）治疗通过抑制雅普/TAZ表达减弱了牵张诱导的HUASMCs从收缩状态到合成状态的表型转换。其他研究表明，拉伸在抑制Hippo通路中的作用，导致PI 3-激酶（PI 3 K）和磷酸肌醇依赖性激酶（PDK 1）的激活;调节PDK 1和Hippo复合物相互作用的关键分子是Sav 1。这些结果表明，生物力学拉伸诱导的雅普/TAZ活化在促进HUASMCs中动脉粥样硬化酮表型中的重要性。结论：综上所述，我们的研究结果揭示了雅普/TAZ激活参与动脉粥样硬化发病机制的机制。
Background/Aims: Increasing wall stress or biomechanical stretch experienced by arteries influences the initiation of atherosclerotic lesions. This initiation is mediated by Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway. In this study, the functional roles of YAP/TAZ proteins in the regulation of the stretch-mediated programing of human umbilical arterial smooth muscle cells (HUASMCs) to a proliferative phenotype were examined. Methods: HUASMCs were seeded on a Matrigel-coated silicone chamber and subjected to biomechanical stretch for 24 h after 48 h of growth. YAP/TAZ small interfering RNA was used to specifically knockdown YAP/ TAZ expression in HUASMCs. Results: We observed that YAP/TAZ activation via biomechanical stretching is involved in the regulation of critical aspects of the HUASMC phenotypic switch. YAP/TAZ knockdown significantly attenuated the stretch-induced proliferative and pro-inflammatory phenotypes in HUASMCs. Furthermore, treatment with atorvastatin, an anti-atherosclerotic drug, attenuated the stretch-induced phenotypic switch of HUASMCs from the contractile to synthetic state by suppressing YAP/TAZ expression. Additional investigations demonstrated the role of stretch in inhibiting the Hippo pathway, leading to the activation of PI3-kinase (PI3K) and phosphoinositide dependent kinase (PDK1); the key molecule for the regulation of the PDK1 and Hippo complex interaction was Sav1. These results showed the importance of YAP/TAZ activation, induced by biomechanical stretch, in promoting atheroprone phenotypes in HUASMCs. Conclusion: Taken together, our findings revealed a mechanism by which YAP/TAZ activation contributes to the pathogenesis of atherosclerosis.