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

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.

Chen X ，Lin S ，Dai S ，Han J ，Shan P ，Wang W ，Huang Z ，Ye B ，Huang W ... -  《-》

Emodin alleviates myocardial ischemia/reperfusion injury by inhibiting gasdermin D-mediated pyroptosis in cardiomyocytes.

Ye B ，Chen X ，Dai S ，Han J ，Liang X ，Lin S ，Cai X ，Huang Z ，Huang W ... -  《Drug Design Development and Therapy》

Lipopolysaccharide (LPS) Aggravates High Glucose- and Hypoxia/Reoxygenation-Induced Injury through Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis in H9C2 Cardiomyocytes.

Qiu Z ，He Y ，Ming H ，Lei S ，Leng Y ，Xia ZY ... -  《-》

Trimetazidine protects against myocardial ischemia/reperfusion injury by inhibiting excessive autophagy.

Wu S ，Chang G ，Gao L ，Jiang D ，Wang L ，Li G ，Luo X ，Qin S ，Guo X ，Zhang D ... -  《-》

The protective effect of Luteolin on myocardial ischemia/reperfusion (I/R) injury through TLR4/NF-κB/NLRP3 inflammasome pathway.

The purpose of the present study was to investigate the effect of Luteolin(Lut) on myocardial ischemia reperfusion injury and explore the underlying mechanism. Myocardial ischemia reperfusion injury (I/R) model was induced with 30min of left anterior descending (LAD) occlusion followed by 24h of reperfusion. In vivo, the rats were randomly divided into 5 groups: (1)Sham, (2)I/R, (3)I/R+Lut(40mg/kg), (4)I/R+Lut(80mg/kg) and (5)I/R+Lut(160mg/kg). In vitro, the H9c2 cells were assigned to five groups: (1)control, (2)hypoxia-reoxygenation(H/R), (3)H/R+Lut(5μM), (4)H/R+Lut(10μM) and (5)H/R+Lut(20μM). The H9c2 cells were stimulated with H/R protocol in the presence or absence of TAK-242, a TLR4 inhibitor. As a result, Lut ameliorated myocardial ischemia reperfusion injury and hypoxia-reoxygenation as evidenced by triphenyl tetrazolium chloride (TTC) staining and MTT assay, respectively. Lut was founded to decrease the levels of aspartate transaminase(AST), creatine phosphokinase-isoenzyme (CK-MB) and lactate dehydrogenase (LDH) in serum. Moreover, Lut could reduce the contents of interleukin-1β(IL-1β), interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α) in serum of rats and supernant of H9c2 cells. In addition, Lut remarkably downregulated the expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear factor kappa B (NF-κB). Lut also inhibited the upregulations of inflammasome components, such as NOD-like receptor 3(NLRP3), apoptosis-associated speck-like protein containing CARD(ASC) in I/R-induced rats and H/R-induced H9c2 cells. In conclusion, Lut exhibited strong favorable cardioprotective effect on myocardial I/R injury which might be related to the down-regulation of the TLR4-meidated NF-κB/NLRP3 inflammasome in vivo and in vitro.

Zhang X ，Du Q ，Yang Y ，Wang J ，Dou S ，Liu C ，Duan J ... -  《-》