Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
The First Clinical College, Chongqing Medical University, Chongqing, China.
J Drug Target. 2021 Jun;29(5):551-561. doi: 10.1080/1061186X.2020.1868478. Epub 2021 Jan 7.
Metformin has been shown to protect myocardial ischaemia/reperfusion or hypoxia/reoxygenation injury. In our current study, we investigated the effects of metformin on autophagy and its possible underlying mechanisms in myocardial infarction (MI) model and oxygen-glucose deprivation (OGD) model. A rat model of MI was made by ligating coronary artery study. Metformin (200 mg/kg/day) could improve cardiac function, prevent rats from MI-induced injury by reducing myocardial infarct size and apoptosis. Moreover, metformin furtherly promoted autophagy by increasing the protein expression of LC3-II, ATG5, ATG7 and Beclin1, and by involving AMPK pathway during MI. H9c2 cells were treated with metformin (4 mM) study to assess its effects after exposure to OGD. Metformin increased cell viability and inhibited OGD-induced LDH synthesis and cell apoptosis. Furthermore, metformin increased autophagosome formations as well as expression of autophagy-related proteins, promoted autophagic flux. In addition, metformin augmented the protein level of Bcl-2 and diminished the protein levels of Bax and cleaved caspase-3. Metformin also upregulated p-AMPK expression. Nevertheless, the above-mentioned effects of metformin on H9c2 cells were remarkably eliminated by compound C (an AMPK inhibitor). In summary, we displayed that metformin protected cardiomyocytes against OGD-induced injury and apoptosis by promoting autophagic flux through the AMPK pathway.
二甲双胍已被证明可保护心肌缺血/再灌注或缺氧/复氧损伤。在本研究中，我们研究了二甲双胍在心肌梗死（MI）模型和氧葡萄糖剥夺（OGD）模型中对自噬的影响及其可能的机制。结扎冠状动脉造成大鼠 MI 模型，研究发现二甲双胍（200mg/kg/天）可改善心脏功能，通过减少心肌梗死面积和细胞凋亡，防止大鼠发生 MI 损伤。此外，在 MI 期间，二甲双胍通过增加 LC3-II、ATG5、ATG7 和 Beclin1 的蛋白表达，并涉及 AMPK 途径，进一步促进自噬。用二甲双胍（4mM）处理 H9c2 细胞，评估其在暴露于 OGD 后的作用。二甲双胍增加细胞活力，抑制 OGD 诱导的 LDH 合成和细胞凋亡。此外，二甲双胍增加自噬小体的形成以及自噬相关蛋白的表达，促进自噬流。此外，二甲双胍增加 Bcl-2 的蛋白水平，减少 Bax 和 cleaved caspase-3 的蛋白水平。二甲双胍还上调 p-AMPK 的表达。然而，化合物 C（一种 AMPK 抑制剂）显著消除了二甲双胍对 H9c2 细胞的上述作用。总之，我们表明二甲双胍通过 AMPK 途径促进自噬流，从而保护心肌细胞免受 OGD 诱导的损伤和凋亡。
