microRNA-126a-5p通过抑制Hspb8表达加重心肌缺血再灌注损伤
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microRNA-126a-5p enhances myocardial ischemia-reperfusion injury through suppressing Hspb8 expression
背景与目的：研究发现某些基因参与了心肌缺血再灌注 (M-I/R)损伤，如microRNA-320、microRNA-103/ 107、microRNA-141和microRNA-21在心脏发育和心肌I/R损伤中起着重要作用。
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方法：本研究中，通过制作M-I/R损伤小鼠模型，用高通量测序microRNA表达分析证明microRNA-126a-5p与M-I/R损伤有关，并进一步研究microRNA-126a-5p在小鼠M-I/R损伤中的表达和功能。
结果：本研究观察到microRNA-126a-5p在M-I/R小鼠中呈现高表达，并且血清中LDH和CK-MB（损伤标志物）的表达水平增加。H2O2和缺氧/复氧（H/R）处理以浓度依赖性和时间依赖性的方式显著增加H9C2细胞中microRNA-126a-5p的表达。此外，H9C2细胞中的microRNA-126a-5p过表达会抑制细胞存活率，但增加了LDH释放和半胱天冬酶-3活性。基于血流动力学参数测量到的心脏功能分析显示，M-I/R损伤小鼠中抑制microRNA-126a-5p表达可逆转M-I/R损伤所引起的症状。食道超声心动图显示，与M-I/R损伤小鼠相比，经microRNA-126a-5p抑制剂处理后的M-I/R损伤小鼠的 LVIDd和LVIDs值均降低，而LVFS %和LVEF %增加。生物信息学分析显示，心肌保护蛋白Hspb8是microRNA-126a-5p的作用靶点。
结论：研究结果表明，microRNA-126a-5p在M-I/R小鼠模型中上调，并通过抑制Hspb8的表达加重体内M-I/R损伤，这可能为M-I/R损伤潜在治疗靶点的发展提供理论依据。
Jiang B1, Liu Y1, Liang P2,et al.microRNA-126a-5p enhances myocardial ischemia-reperfusion injury through suppressing Hspb8 expression[J].Oncotarget, Oct 7，2017;8(55):94172-94187
BACKGROUND:Previously, we found several genes are involved in myocardial ischemiareperfusion (M-I/R) injury.
METHODS:In this report, we first developed a mouse model of M-I/R injury and demonstrated microRNA-126a-5p was associated with the M-I/R injury by using high-throughput microRNA expression analysis. We further investigated the expression and function of microRNA-126a-5p during mouse M-I/R injury.
RESULTS:We observed high expression of microRNA-126a-5p in the M-I/R mice and increased levels of LDH and CK-MB (damage markers) in the serum. H2O2 and hypoxia/reoxygenation (H/R) treatment significantly increased the expression of microRNA-126a-5p in H9C2 cells in concentration- and time-dependent manners. Moreover, microRNA-126a-5p overexpression in H9C2 cells inhibited cell viability but increased LDH release and caspase 3 activity. Cardiac function analysis based on the measurements of hemodynamic parameters showed that microRNA-126a-5p expression ablation in M-I/R injured mice led to the reversal of the symptoms caused by M-I/R injury. Transesophageal echocardiography also revealed that the values of LVIDd and LVIDs were decreased while the values of LVFS% and LVEF% were increased in M-I/R injured mice after treatment with microRNA-126a-5p inhibitor, compared with the M-I/R injured mice treated with the control. Bioinformatic analysis demonstrated that Hspb8, a protective protein in myocardium, was the target of microRNA-126a-5p.
CONCLUSIONS:Thus,these findings indicated that microRNA-126a-5p was up-regulated in mouse M-I/R model and promoted M-I/R injury in vivo through suppressing the expression of Hspb8, which may shed light on the development of potential therapeutic target for M-I/R injury.
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