Trimetazidine affects pyroptosis by targeting GSDMD in myocardial ischemia/reperfusion injury

• DOI: 10.1007/s00011-021-01530-6
• Publication Date: 2022-01-07T00:03:47Z
• Authors: Xudong Chen; Shuang Lin; Shanshan Dai; Jibo Han; Peiren Shan; Weiqi Wang; Zhouqing Huang; Bozhi Ye; Weijian Huang
• Keywords: Male; Pore Forming Cytotoxic Proteins; 0303 health sciences; NF-kappa B; Trimetazidine; Myocardial Reperfusion Injury; Phosphate-Binding Proteins; Rats; 3. Good health; Rats, Sprague-Dawley; Toll-Like Receptor 4; 03 medical and health sciences; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Animals; Myocytes, Cardiac; Signal Transduction

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.