Chen Xudong, Lin Shuang, Dai Shanshan, Han Jibo, Shan Peiren, Wang Weiqi, Huang Zhouqing, Ye Bozhi, Huang Weijian
Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Department of Cardiology, Ningbo Hangzhou Bay Hospital, Ningbo, Zhejiang, People's Republic of China.
Inflamm Res. 2022 Feb;71(2):227-241. doi: 10.1007/s00011-021-01530-6. Epub 2022 Jan 7.
Trimetazidine (TMZ) exerts a strong inhibitory effect on ischemia/reperfusion (I/R) injury. Inflammation plays a key role in I/R injury. We hypothesized that TMZ may protect cardiomyocytes from I/R injury by inhibiting inflammation.
The left anterior descending coronary artery was ligated for 30 min followed by 6 h of reperfusion to establish a model of I/R injury. H9c2 cardiomyocytes were subjected to 2 h of hypoxia and 3 h of normoxic conditions to establish a model of hypoxia/reoxygenation (H/R) injury. We monitored the change in pyroptosis by performing Western blot analysis, microscopy and ELISA.
I/R and H/R treatment stimulated gasdermin D-N domain (GSDMD-N) expression in cardiomyocytes (sham onefold vs. I/R 2.5-fold; control onefold vs. H/R 2.0-fold). Moreover, TMZ increased the viability of H9c2 cardiomyocytes subjected to H/R treatment (H/R 65.0% vs. H/R + TMZ 85.3%) and reduced the infarct size in vivo (I/R 47.0% vs. I/R + TMZ 28.3%). H/R and I/R treatment increased the levels of TLR4, MyD88, phospho-NF-κB p65 and the NLRP3 inflammasome; however, TMZ reduced the expression of these proteins. Additionally, TMZ inhibited noncanonical inflammasome signaling induced by I/R injury.
In summary, TMZ alleviated pyroptosis induced by myocardial I/R injury through the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, TMZ represents an alternative treatment for myocardial I/R injury.
曲美他嗪（TMZ）对缺血/再灌注（I/R）损伤具有强大的抑制作用。炎症在I/R损伤中起关键作用。我们假设TMZ可能通过抑制炎症来保护心肌细胞免受I/R损伤。
结扎左冠状动脉前降支30分钟，随后再灌注6小时以建立I/R损伤模型。将H9c2心肌细胞置于缺氧2小时和常氧3小时的条件下以建立缺氧/复氧（H/R）损伤模型。我们通过蛋白质免疫印迹分析、显微镜检查和酶联免疫吸附测定来监测细胞焦亡的变化。
I/R和H/R处理刺激心肌细胞中gasdermin D-N结构域（GSDMD-N）的表达（假手术组为1倍，I/R组为2.5倍；对照组为1倍，H/R组为2.0倍）。此外，TMZ提高了接受H/R处理的H9c2心肌细胞的活力（H/R组为65.0%，H/R + TMZ组为85.3%），并减小了体内梗死面积（I/R组为47.0%，I/R + TMZ组为28.3%）。H/R和I/R处理增加了Toll样受体4（TLR4）、髓样分化因子88（MyD88）、磷酸化核因子κB p65（phospho-NF-κB p65）和NLRP3炎性小体的水平；然而，TMZ降低了这些蛋白质的表达。此外，TMZ抑制了由I/R损伤诱导的非经典炎性小体信号传导。
总之，TMZ通过TLR4/MyD88/NF-κB/NLRP3炎性小体途径减轻了心肌I/R损伤诱导的细胞焦亡。因此，TMZ是心肌I/R损伤的一种替代治疗方法。
