Metformin Protects against H(2)O(2)-Induced Cardiomyocyte Injury by Inhibiting the miR-1a-3p/GRP94 Pathway.
Metformin Protects against H(2)O(2)-Induced Cardiomyocyte Injury by Inhibiting the miR-1a-3p/GRP94 Pathway.
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二甲双胍通过抑制 miR-1a-3p/GRP94 途径预防 H2O2 诱导的心肌细胞损伤
DOI：
10.1016/j.omtn.2018.09.001
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发表时间：
2018-12-07
期刊：
影响因子：
--
通讯作者：
Du Z
中科院分区：
文献类型：
--
作者：
Zhang Y;Liu X;Zhang L;Li X;Zhou Z;Jiao L;Shao Y;Li M;Leng B;Zhou Y;Liu T;Liu Q;Shan H;Du Z
缺血再灌注(I/R)损伤是缺血心脏再灌注治疗的主要副作用。目前尚无有效预防氧化应激诱导的心肌细胞凋亡所致的心肌损伤的治疗方法。二甲双胍被证明具有潜在的心脏保护作用和减少心脏事件的能力，但确切的机制尚不清楚。在这里，我们的目的是确认和研究潜在的二甲双胍抗I/R损伤的机制，以应对氧化应激。我们发现，在体外培养的新生大鼠心室细胞(NRVCs)和小鼠心脏I/R损伤后，miR-1a-3p的表达显著增加。MIR-1a-3p靶向GRP94的3‘UTR，导致未折叠或错误折叠的蛋白质积累，导致内质网(ER)应激。结果表明，C/eBPβ通过与其启动子结合，直接诱导miR-1a-3p表达上调。此外，作为一种直接变构AMPK激动剂，二甲双胍可激活AMPK，并显著降低C/EBPβ和miR-1a-3p的水平。综上所述，二甲双胍通过AMPK/C/EBPβ/miR-1a-3p/GRP94途径保护心肌细胞免受H_2O_2损伤，提示二甲双胍可能用于I/R损伤的治疗。
Ischemia-reperfusion (I/R) injury is a major side effect of the reperfusion treatment of the ischemic heart. Few therapies are available for the effective prevention of this injury caused by the oxidative stress-induced cardiomyocyte apoptosis. Metformin was shown to have a potential cardiac protective effect and ability to reduce cardiac events, but the exact mechanism remains unclear. Here, we aimed to confirm and investigate the mechanisms underlying potential metformin activity against I/R injury in response to oxidative stress. We determined that the expression of miR-1a-3p was significantly increased in neonatal rat ventricular cells (NRVCs), which were exposed to H2O2in vitro and in the hearts of mice that underwent the I/R injury. MiR-1a-3p was shown to target the 3′ UTR of GRP94, which results in the accumulation of un- or misfolded proteins, leading to the endoplasmic reticulum (ER) stress. The obtained results demonstrated that C/EBP β directly induces the upregulation of miR-1a-3p by binding to its promoter. Furthermore, as a direct allosteric AMPK activator, metformin was shown to activate AMPK and significantly reduce C/EBP β and miR-1a-3p levels compared with those in the control group. In conclusion, metformin protects cardiomyocytes against H2O2 damage through the AMPK/C/EBP β/miR-1a-3p/GRP94 pathway, which indicates that metformin may be applied for the treatment of I/R injury.
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影响因子：
9.2
作者：
Lee YE;Hong CY;Lin YL;Chen RM
通讯作者：
Chen RM
DOI：
10.1073/pnas.0602831103
发表时间：
2006-06-06
影响因子：
11.1
作者：
Rao, Prakash K.;Kumar, Roshan M.;Lodish, Harvey F.
通讯作者：
Lodish, Harvey F.
影响因子：
37.8
作者：
KLONER, RA;GIACOMELLI, F;BELLOWS, S
通讯作者：
BELLOWS, S
影响因子：
82.9
作者：
Yang, Baofeng;Lin, Huixian;Wang, Zhiguo
通讯作者：
Wang, Zhiguo
影响因子：
10.8
作者：
Kewalramani, Girish;Puthanveetil, Prasanth;Rodrigues, Brian
通讯作者：
Rodrigues, Brian