MiR-15b-5p Regulates Collateral Artery Formation by Targeting AKT3 (Protein Kinase B-3)
MiR-15b-5p Regulates Collateral Artery Formation by Targeting AKT3 (Protein Kinase B-3)
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MiR-15b-5p 通过靶向 AKT3（蛋白激酶 B-3）调节侧支动脉形成
DOI：
10.1161/atvbaha.116.308905
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发表时间：
2017-05-01
影响因子：
8.7
通讯作者：
Zhang, Guo-Gang
中科院分区：
文献类型：
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作者：
Zhu, Ling-Ping;Zhou, Ji-Peng;Zhang, Guo-Gang
目的-鉴定在侧支动脉发育良好或发育不良的严重冠心病中差异表达的循环 microRNA，并研究其在体内和体外的作用机制。方法和结果-在我们的研究中，我们鉴定了一种低表达的循环 microRNA，miR-15b-5p，但它表征了具有足够冠状侧支动脉功能的患者。此外，在小鼠后肢缺血模型中，原位杂交发现，假手术组中miR-15b-5p在内收肌血管内皮细胞中特异性表达，并且在股动脉结扎后显着下调。过表达的 miR-15b-5p 显着抑制小鼠的动脉生成和血管生成。体外，在基础和血管内皮生长因子刺激下，功能丧失或功能获得研究表明，miR-15b-5p显着促进或抑制内皮细胞的迁移和增殖。我们确定 AKT3（蛋白激酶 B-3）是 miR-15b-5p 的直接靶标。有趣的是，通过注射 Chol-AKT3-siRNA 来消除 AKT3 缺陷，可以明显抑制小鼠股骨结扎后的动脉生成和血液灌注的恢复。 结论 - 这些结果表明，循环 miR-15b-5p 是区分侧支发育良好或发育不良的患者的合适生物标志物。此外，miR-15b-5p是动脉生成和血管生成的关键调节因子，可能代表缺血性疾病的潜在治疗靶点。
Objective-To identify circulating microRNAs that are differentially expressed in severe coronary heart disease with well or poorly developed collateral arteries and to investigate their mechanisms of action in vivo and in vitro.Approach and Results-In our study, we identified a circulating microRNA, miR-15b-5p, with low expression that, nevertheless, characterized patients with sufficient coronary collateral artery function. Moreover, in murine hindlimb ischemia model, in situ hybridization identified that miR-15b-5p was specifically expressed in vascular endothelial cells of adductors in sham group and was remarkably downregulated after femoral artery ligation. Overexpressed miR-15b-5p significantly inhibited arteriogenesis and angiogenesis in mice. In vitro, both under basal and vascular endothelial growth factor stimulation, loss-of-function or gain-of-function studies suggested that miR-15b-5p significantly promoted or depressed the migration and proliferation of endothelial cells. We identified AKT3 (protein kinase B-3) as a direct target of miR-15b-5p. Interestingly, AKT3 deficiency by injection with Chol-AKT3-siRNA obviously suppressed arteriogenesis and the recovery of blood perfusion after femoral ligation in mice.Conclusions-These results indicate that circulating miR-15b-5p is a suitable biomarker for discriminating between patients with well-developed or poorly developed collaterals. Moreover, miR-15b-5p is a key regulator of arteriogenesis and angiogenesis, which may represent a potential therapeutic target for ischemic disease.