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Cardiac rupture (CR) is a catastrophic complication of acute myocardial infarction (MI). At present, there are no effective pharmacological strategies for preventing post-MI rupture. Here we investigated the effect of trimetazidine (TMZ) on post-MI cardiac rupture and its underlying mechanisms of action.
MI models were induced by left coronary artery ligation in male C57BL/6 mice, with shams undergoing the same operation without coronary artery ligation. The operated mice were randomly divided into 4 groups: sham+saline, sham+TMZ, MI+saline and MI+TMZ (20mg/kg/day) treatment group. Animals allocated to the rupture incidence were closely monitored for 7 days; autopsy was performed once animals were found dead to determine the reason of death, and infarct size was determined. Heart function was detected by echocardiography. Oxidative stress markers were analyzed by Western blotting. Cultured neonatal cardiomyocytes and H9c2(2-1) were exposed to normoxia or anoxia and treated with TMZ.
Since CR in mice mostly happen within the first week after MI, we observed the incidence of CR of MI mice for one week. We found that the CR rate of mice treated with TMZ was significantly lower than the saline-treated group (34.4% vs. 19.4%, P<0.05). To investigate the mechanism of the effect of TMZ on CR, we examined the expression of MMP2, MMP9 in the cardiac tissues of the sham-operated and MI groups of mice. The results showed that the MMP2, MMP9 expression in the TMZ-treated group was significantly lower than the saline-treated group. Further, we found that ROS and H2O2 level increased dramatically after MI, and TMZ treatment abolished level of ROS and H2O2. To further examine the action of TMZ on MMP2, MMP9 expression, we pretreated H9c2(2-1) and primary cardiomyocytes with anoxia and found that TMZ treatment increased expression of MMP2, MMP9. TMZ pretreatment markedly decreased the expression of MMP2, MMP9, and reduced level of ROS and H2O2 by anoxia.
TMZ prevents cardiac rupture through inhibition of oxidative stress, which is attributable to the down-regulation of MMP2, MMP9 expression. Our findings suggested that early administration of TMZ to patients with acute MI is a potential preventive approach for CR.
This study was supported by grants from the National Natural Science Foundation of China (81600213), Beijing Natural Science Foundation (7141003).