Yu Fei, Liu Fen, Luo Jun-Yi, Zhao Qian, Wang Hong-Li, Fang Bin-Bin, Li Xiao-Mei, Yang Yi-Ning
Xinjiang Key Laboratory of Cardiovascular Disease, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Ann Transl Med. 2022 Nov;10(22):1238. doi: 10.21037/atm-22-5149.
Diabetes can increase the risk of coronary heart disease, and also increase the mortality rate of coronary heart disease in diabetic patients. Although reperfusion therapy can preserve the viable myocardium, fatal reperfusion injury can also occur. Studies have shown that diabetes can aggravate myocardial ischemia-reperfusion injury, ERK1/2 can reduce myocardial ischemia-reperfusion injury, but its mechanism in hyperglycemic myocardial ischemia-reperfusion injury is unclear. This study sought to explore the mechanism of extracellular signal-regulated kinase 1/2 (ERK1/2) in hyperglycemic myocardial ischemia reperfusion (I/R) injury.
H9C2 cardiomyocytes were treated with high-glucose (HG) medium plus I/R stimulation to establish a hyperglycemia I/R model The cells were treated with LM22B-10 (an ERK activator) or transfected with the constitutive activation of the mitogen-activated protein kinase 1 () gene. Myocardial cell apoptosis, mitochondria functional-related indicators, the oxidative stress indexes, and the expression levels of ERK1/2 protein were detected.
The HG I/R injury intervention caused an increase in the ratio of apoptotic cardiomyocytes (P<0.05), but the phosphorylation level of the ERK1/2 protein did not increase further. Administering LM22B-10 or transfecting the gene significantly activated the phosphorylation levels of ERK1/2 protein and reduced the proportion of cardiomyocyte apoptosis (P<0.05). HG I/R injury increased mitochondrial fission and reduced membrane potential. The intervention reduced the number of punctate mitochondria, increased the average network structure size and median branch length (P<0.01), increased the median network structure size and average branch length (P<0.05), and reduced the colocalization of Drp1 (Dynamin-Related protein1)/TOMM20 (Mitochondrial outer membrane translocation enzyme 20) (P<0.05) and Drp1 with serine 616 phosphorylation (Drp1s616) phosphorylation (P<0.01), thereby reducing mitochondrial fission, increasing membrane potential and mitochondrial function. HG I/R injury increased the level of oxidative stress, while administering LM22B-10 or transfecting the gene reduced the level of oxidative stress (P<0.01).
Targeting the activation of ERK1/2 protein phosphorylation reduced mitochondrial fission, increased membrane potential and mitochondrial function, reduced oxidative stress and myocardial cell apoptosis, and alleviated hyperglycemia myocardial I/R injury.
糖尿病会增加冠心病风险，还会提高糖尿病患者冠心病的死亡率。尽管再灌注治疗可保留存活心肌，但也可能发生致命的再灌注损伤。研究表明，糖尿病会加重心肌缺血再灌注损伤，细胞外信号调节激酶1/2（ERK1/2）可减轻心肌缺血再灌注损伤，但其在高血糖心肌缺血再灌注损伤中的机制尚不清楚。本研究旨在探讨细胞外信号调节激酶1/2（ERK1/2）在高血糖心肌缺血再灌注（I/R）损伤中的机制。
用高糖（HG）培养基加I/R刺激处理H9C2心肌细胞，建立高血糖I/R模型。细胞用LM22B-10（一种ERK激活剂）处理或转染有丝分裂原活化蛋白激酶1（）基因的组成型激活物。检测心肌细胞凋亡、线粒体功能相关指标、氧化应激指标以及ERK1/2蛋白的表达水平。
HG I/R损伤干预导致凋亡心肌细胞比例增加（P<0.05），但ERK1/2蛋白的磷酸化水平未进一步升高。给予LM22B-10或转染基因显著激活了ERK1/2蛋白的磷酸化水平，并降低了心肌细胞凋亡比例（P<0.05）。HG I/R损伤增加了线粒体分裂并降低了膜电位。干预减少了点状线粒体数量，增加了平均网络结构大小和中位分支长度（P<0.01），增加了中位网络结构大小和平均分支长度（P<0.05），并减少了动力相关蛋白1（Drp1）/线粒体膜转位酶20（TOMM20）的共定位（P<0.05）以及丝氨酸616磷酸化的Drp1（Drp1s616）的磷酸化（P<0.01），从而减少线粒体分裂，增加膜电位和线粒体功能。HG I/R损伤增加了氧化应激水平，而给予LM22B-10或转染基因降低了氧化应激水平（P<0.01）。
靶向激活ERK1/2蛋白磷酸化可减少线粒体分裂，增加膜电位和线粒体功能，降低氧化应激和心肌细胞凋亡，减轻高血糖心肌I/R损伤。
