MicroRNA-210 as a novel therapy for treatment of ischemic heart disease.
MicroRNA-210 as a novel therapy for treatment of ischemic heart disease.
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DOI：
10.1161/circulationaha.109.928424
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发表时间：
2010-09-14
期刊：
影响因子：
37.8
通讯作者：
Wu JC
中科院分区：
文献类型：
--
作者：
Hu S;Huang M;Li Z;Jia F;Ghosh Z;Lijkwan MA;Fasanaro P;Sun N;Wang X;Martelli F;Robbins RC;Wu JC
MiRNAs参与多种重要功能，包括调节细胞分化、增殖、血管生成和细胞凋亡。在这里，我们假设miR-210可以通过上调心脏血管生成和抑制细胞凋亡来恢复心肌梗死后的心功能。利用miRNA芯片，我们首次发现在低氧暴露48小时后，与凋亡细胞相比，miR-210在活的小鼠HL-1心肌细胞中高表达。我们通过聚合酶链式反应证实miR-210在这些细胞中得到了强有力的诱导。采用功能获得和功能丧失的方法研究miR-210的体外治疗潜力。与对照组相比，miR-210可上调多种血管生成因子，抑制caspase活性，防止细胞凋亡。随后，成年FVB小鼠心肌内注射携带miR-210前体的微环(MC-210)、携带miR-scr的微环(MC-SCR)或假手术。8周后，超声心动图显示，与MC-SCR对照组相比，MC-210组的左室短轴缩短率(FS)有显著改善。组织学分析证实细胞凋亡减少，新生血管增加。最后，通过进一步的实验验证，证实了miR-210的两个潜在靶点，即EfNA3和PTP1B，它们参与了血管生成和细胞凋亡。在心肌梗死小鼠模型中，MIR-210可以促进血管生成，抑制细胞凋亡，改善心功能。它代表了一种潜在的治疗缺血性心脏病的新方法。
MiRNAs are involved in various critical functions, including the regulation of cellular differentiation, proliferation, angiogenesis, and apoptosis. Here we hypothesize that miR-210 can rescue cardiac function after myocardial infarction by up-regulation of angiogenesis and inhibition of cellular apoptosis in the heart. Using miRNA microarrays, we first showed that miR-210 was highly expressed in live mouse HL-1 cardiomyocytes compared with apoptotic cells after 48 hours of hypoxia exposure. We confirmed by PCR that miR-210 was robustly induced in these cells. Gain-of-function and loss-of-function approaches were used to investigate miR-210 therapeutic potential in vitro. Following transduction, miR-210 can upregulate several angiogenic factors, inhibit caspase activity, and prevent cell apoptosis compared with control. Afterwards, adult FVB mice underwent intramyocardial injections with minicircle (MC) vector carrying miR-210 precursor (MC-210), minicircle carrying miR-scramble (MC-Scr), or sham surgery. At 8 weeks, echocardiography showed a significant improvement of left ventricular fractional shortening (FS) in the MC-210 group compared to MC-Scr control. Histological analysis confirmed decreased cellular apoptosis and increased neovascularization. Finally, two potential targets of miR-210, Efna3 and Ptp1b, involved in angiogenesis and apoptosis were confirmed via additional experimental validation. miR-210 can improve angiogenesis, inhibit apoptosis, and improve cardiac function in a murine model of myocardial infarction. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.