Drug-eluting stent specifically designed to target vascular smooth muscle cell phenotypic modulation attenuated restenosis through the YAP pathway
Drug-eluting stent specifically designed to target vascular smooth muscle cell phenotypic modulation attenuated restenosis through the YAP pathway
复制标题
专门设计用于通过 YAP 途径针对血管平滑肌细胞表型调节减轻再狭窄的药物洗脱支架
DOI：
10.1152/ajpheart.00089.2019
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发表时间：
2019-09-01
影响因子：
4.8
通讯作者：
Zhu, Yuelin
中科院分区：
文献类型：
--
作者：
Huang, Chen;Zhang, Wenwen;Zhu, Yuelin
血管平滑肌细胞（SMC）表型调节有助于再狭窄的发展。在本研究中，索拉非尼洗脱支架被专门设计用于SMC表型调节以抑制支架内再狭窄。新鲜分离的大鼠主动脉SMC收缩蛋白表达水平较高，但SMCs在10%胎牛血清中培养1周后，其表达显著降低。索拉非尼治疗后，SMC收缩蛋白表达明显上调。我们进一步观察到，在索拉非尼治疗后，yes相关蛋白（YAP）的表达以剂量依赖的方式减弱。慢病毒过表达YAP逆转了索拉非尼诱导的SMC收缩蛋白的表达，增加了cyclin d的表达。机制上，索拉非尼通过YAP与心肌的竞争性结合来调节血清反应因子-心肌素（SRF-心肌）复合物，并增加SRF与完整染色质中SMC特异性收缩基因含carg区域的结合，从而控制平滑肌特异性基因的转录活性。在兔颈动脉模型中，索拉非尼洗脱支架（SFES）显著抑制支架内再狭窄和上调SMC收缩蛋白表达。在体内，YAP过表达阻断了SFES的抗再狭窄作用，抑制了可收缩平滑肌特异性基因，表明SFES通过YAP介导的SMC表型调节减轻了支架内再狭窄。我们证明SFES通过yap介导的SMC表型调节减轻支架内再狭窄。药物洗脱支架靶向SMC表型调节是治疗闭塞性血管疾病的一种有吸引力的治疗方法。在目前的研究中，我们证明了索拉非尼调节平滑肌细胞（SMC）从增殖状态到收缩状态的表型调节。索拉非尼诱导心肌素-血清反应因子相互作用，并通过yes相关蛋白途径增加SMC收缩基因转录。此外，局部递送索拉非尼调节SMC表型调节在药物洗脱支架的设计中是一种很有前途的策略。
Vascular smooth muscle cell (SMC) phenotypic modulation contributes to the development of restenosis. A sorafenib-eluting stent was specifically designed to target SMC phenotypic modulation to inhibit in-stent restenosis in the present study. SMC contractile protein from the freshly isolated rat aorta was expressed at a high level, but its expression was dramatically reduced after SMCs were cultured in 10% FBS for 1 wk. After sorafenib treatment, SMC contractile protein expression was markedly upregulated. We further observed that Yes-associated protein (YAP) expression was attenuated after sorafenib treatment in a dose-dependent manner. Overexpression of YAP by lentivirus reversed the expression of sorafenib-induced SMC contractile protein and increased the expression of cyclin D. Mechanistically, sorafenib regulated the serum response factor-myocardin (SRF-Myocd) complex through competitive binding of YAP to Myocd and increased SRF binding to CArG-containing regions of SMC-specific contractile genes within intact chromatin, thereby controlling the activity of smooth muscle-specific gene transcription. In a rabbit carotid model, the sorafenib-eluting stent (SFES) dramatically inhibited in-stent restenosis and upregulated SMC contractile protein expression. Overexpression of YAP blocked the antirestenosis effect of SFES and repressed contractile smooth muscle-specific genes in vivo, indicating that SFES attenuated in-stent restenosis through YAP-mediated SMC phenotypic modulation. We demonstrated that SFES attenuated in-stent restenosis through YAP-mediated SMC phenotypic modulation. Targeting SMC phenotypic modulation by drug-eluting stent represents an attractive therapeutic approach for the treatment of occlusive vascular diseases.NEW & NOTEWORTHY In the present study, we demonstrated that sorafenib regulates smooth muscle cell (SMC) phenotypic modulation from a proliferative to a contractile state. Sorafenib induced a myocardin-serum response factor interaction and increased SMC contractile gene transcription through the Yes-associated protein pathway. Moreover, local delivery of sorafenib regulating SMC phenotypic modulation represents a promising strategy in the design of drug-eluting stents.