Danhong injection enhances angiogenesis after myocardial infarction by activating MiR-126/ERK/VEGF pathway
Danhong injection enhances angiogenesis after myocardial infarction by activating MiR-126/ERK/VEGF pathway
复制标题
丹红注射液通过激活MiR-126/ERK/VEGF通路增强心肌梗死后血管生成
DOI：
10.1016/j.biopha.2019.109538
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发表时间：
2019-12-01
影响因子：
7.5
通讯作者：
Liu, Hong-Xu
中科院分区：
文献类型：
--
作者：
Li, Si-Nai;Li, Ping;Liu, Hong-Xu
背景/目的：丹红注射液（DHI）是一种用于缓解心血管疾病的中药。本研究旨在探讨DHI对梗死后血管生成的影响及作用机制，特别是血管生成的表观遗传调控。方法：结扎左冠状动脉前降支诱导心肌梗死（MI）小鼠模型。 MI 后立即开始为期 4 周的每天腹腔注射 DHI 治疗。通过超声心动图和免疫染色测量心肌梗死后心脏功能、病理学和血管生成的变化。采用基质胶管形成和划痕实验评估 DHI 对缺氧人脐静脉内皮细胞 (HUVEC) 增殖和迁移的影响。通过定量实时聚合酶链反应 (qRT-PCR) 测量 miR-126、Spred-1 和血管生成相关 mRNA 的表达。 Western blot分析检测相关蛋白的表达以及细胞外信号调节激酶（ERK）和蛋白激酶B的磷酸化水平。使用 antagomir-126 进行功能丧失研究。结果：MI 后 4 周，DHI 治疗的小鼠梗塞面积显着减小，射血分数提高，毛细血管密度增加。此外，DHI 还促进缺氧 HUVEC 的增殖和迁移。 qRT-PCR 和 Western blot 分析显示，DHI 干预上调 miR-126，抑制 Spred-1 表达，并激活 ERK 通路，但不激活 Akt 通路。功能丧失研究表明，antagomir-126 阻断了 DHI 的促血管生成作用，涉及 ERK/血管内皮生长因子 (VEGF) 通路。结论：DHI 通过激活 miR-126/ERK/VEGF 通路增强 MI 后梗塞后血管生成。
Background/aim: Danhong injection (DHI) is a Chinese drug used for relieving cardiovascular diseases. This study aimed to identify the effect and mechanism of action of DHI on post-infarct angiogenesis, especially the epigenetic regulation of angiogenesis.Methods: A myocardial infarction (MI) mouse model was induced by ligating the left anterior descending coronary artery. A 4-week daily treatment with or without DHI via intraperitoneal injection was started immediately following MI. The changes in cardiac function, pathology, and angiogenesis following MI were measured by echocardiography and immunostaining. Matrigel tube formation and scratch wound assays were used to evaluate the effect of DHI on the proliferation and migration of hypoxic human umbilical vein endothelial cells (HUVECs). The expression of miR-126, Spred-1, and angiogenesis-related mRNAs was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of related proteins and the phosphorylated levels of extracellular signal-regulated kinase (ERK) and protein kinase B were detected by Western blot analysis. The loss-of-function study was performed using antagomir-126.Results: The DHI-treated mice had significantly reduced infarct area, improved ejection fraction, and increased capillary density 4 weeks after MI. Also, DHI promoted the proliferation and migration of hypoxic HUVECs. The qRT-PCR and Western blot analysis revealed that DHI intervention upregulated miR-126, suppressed Spred-1 expression, and activated the ERK pathway, but not the Akt pathway. The loss-of-function study showed the blockade of the pro-angiogenic effect of DHI by antagomir-126 involving the ERK/vascular endothelial growth factor (VEGF) pathway.Conclusion: DHI enhanced post-infarct angiogenesis after MI by activating the miR-126/ERK/VEGF pathway.