Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China; Department of Central Laboratory, Affiliated Hospital of Hebei University, Baoding, China.
Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
Eur J Pharmacol. 2020 Aug 5;880:173140. doi: 10.1016/j.ejphar.2020.173140. Epub 2020 May 6.
The inflammation and proliferation of vascular smooth muscle cells (VSMCs) are the basic pathological feature of proliferative vascular diseases. Tanshinone ⅡA (Tan ⅡA), which is the most abundant fat-soluble element extracted from Salvia miltiorrhiza, has potent protective effects on the cardiovascular system. However, the underlying mechanism is still not fully understood. Here, we show that Tan ⅡA significantly inhibits neointimal formation and decreases VSMC inflammation by upregulating the expression of KLF4 and inhibiting the activation of NFκB signaling. Using a microRNA array analysis, we found that miR-712-5p expression is significantly upregulated in tumor necrosis factor alpha (TNF-α)-treated VSMCs. Loss- and gain-of-function experiments revealed that transfection of miR-712-5p mimic promotes, whereas depletion of miR-712-5p suppresses TNF-α-induced VSMC inflammation, leading to amelioration of intimal hyperplasia induced by carotid artery ligation. Moreover, depletion of miR-712-5p by its antagomir largely abrogates TNF-α-induced VSMC proliferation. Our findings suggest that miR-712-5p mediates the stimulatory effect of TNF-α on VSMC inflammation, and that Tan ⅡA inhibits VSMC inflammation and proliferation in vivo and in vitro by suppression of miR-712-5p expression. Targeting miR-712-5p may be a novel therapeutic strategy to prevent proliferative vascular diseases.
血管平滑肌细胞（VSMCs）的炎症和增殖是增生性血管疾病的基本病理特征。丹参酮Ⅱ A（Tan ⅡA）是从丹参中提取的最丰富的脂溶性成分，对心血管系统有很强的保护作用。然而，其潜在的机制尚不完全清楚。在这里，我们表明 Tan ⅡA 通过上调 KLF4 的表达和抑制 NFκB 信号的激活，显著抑制新生内膜形成和减少 VSMC 炎症。通过 microRNA 阵列分析，我们发现肿瘤坏死因子-α（TNF-α）处理的 VSMCs 中 miR-712-5p 的表达显著上调。失活和功能获得实验表明，miR-712-5p 模拟物的转染促进了 TNF-α诱导的 VSMC 炎症，而 miR-712-5p 的耗竭则抑制了 TNF-α诱导的 VSMC 炎症，从而改善了颈动脉结扎引起的内膜增生。此外，其反义寡核苷酸通过耗竭 miR-712-5p 可显著抑制 TNF-α诱导的 VSMC 增殖。我们的研究结果表明，miR-712-5p 介导了 TNF-α对 VSMC 炎症的刺激作用，而 Tan ⅡA 通过抑制 miR-712-5p 的表达，在体内和体外抑制 VSMC 炎症和增殖。靶向 miR-712-5p 可能是预防增生性血管疾病的一种新的治疗策略。
