Abstract：
Vascular lesions frequently arise as complication in patients diagnosed with diabetes mellitus (DM). Presently, percutaneous coronary intervention (PCI) and antithrombotic therapy serve as primary treatments. However, in-stent restenosis persists as a challenging clinical issue following PCI, lacking sustained and effective treatment. Linarin (LN) exhibits diverse pharmacological activities and is regarded as a potential drug for treating various diseases, including DM. But its specific role in restenosis after vascular injury in DM patients remains unclear. A rat model of diabetes-related restenosis was established to evaluate the role of LN on neointimal hyperplasia. Vascular smooth muscle cells (VSMCs) stimulated by high glucose (HG, 30 mM) underwent LN treatment. Additionally, an overexpression plasmid of A disintegrin and metalloproteinases (ADAM10) was constructed to transfect VSMCs. We employed CCK-8, Brdu, wound-healing scratch, and transwell migration assays to evaluate the proliferation and migration of VSMCs. Furthermore, western blot and immunofluorescence assays were utilized to investigate the expressions of ADAM10 and the downstream Notch signaling pathway in vivo and in vitro models. LN notably alleviated intimal hyperplasia after vascular injury in DM rats and reduced the protein expression of ADAM10, alongside its downstream Notch1 signaling pathway-related proteins (Notch1, NICD and Hes1) in rat carotid artery tissues. LN effectively suppressed the proliferation and migration of VSMCs induced by HG, downregulating the protein expression of ADAM10, Notch1, NICD and Hes1. Moreover, our findings indicated that ADAM10 overexpression significantly reversed LN\'s effects on proliferation, migration, and the expression of Notch1 signaling pathway-related proteins in HG-treated VSMCs. LN demonstrates potential therapeutic efficacy in addressing restenosis after diabetic-related vascular injury, with the ADAM10 mediated Notch signaling pathway playing a pivotal role.
摘要：
在诊断为糖尿病（DM）的患者中，血管病变经常作为并发症出现。目前,经皮冠状动脉介入治疗(PCI)和抗血栓治疗是主要治疗方法.然而,PCI术后支架内再狭窄仍然是一个具有挑战性的临床问题,缺乏持续有效的治疗.linarin（LN）具有多种药理活性，被认为是治疗各种疾病的潜在药物。包括DM。但其在DM患者血管损伤后再狭窄中的具体作用尚不清楚。建立了糖尿病相关再狭窄大鼠模型，以评估LN在新生内膜增生中的作用。高糖刺激的血管平滑肌细胞（VSMC）（HG，30mM)进行LN处理。此外,构建解整合素和金属蛋白酶（ADAM10）的过表达质粒以转染VSMC。我们雇佣了CCK-8Brdu,伤口愈合划痕，和transwell迁移试验来评估VSMC的增殖和迁移。此外，采用westernblot和免疫荧光法检测ADAM10和下游Notch信号通路在体内和体外模型中的表达。LN可显着减轻DM大鼠血管损伤后的内膜增生，并降低ADAM10的蛋白表达，以及其下游Notch1信号通路相关蛋白（Notch1，NICD和Hes1）在大鼠颈动脉组织中的表达。LN能有效抑制HG诱导的VSMCs的增殖和迁移,下调ADAM10、Notch1、NICD和Hes1的蛋白表达。此外，我们的研究结果表明，ADAM10过表达显著逆转LN对增殖的影响，迁移,和Notch1信号通路相关蛋白在HG处理的VSMCs中的表达。LN在解决糖尿病相关血管损伤后的再狭窄方面具有潜在的治疗功效，ADAM10介导的Notch信号通路起着举足轻重的作用。
