Abstract
Myocardial ischemia-reperfusion (I/R) injury caused by revascularization treatment is the leading cause of cardiac damage aggravation in ischemic heart disease. Increasing evidence has unraveled the crucial role of pyroptosis in myocardial I/R injury. Of note, lactylation has been validated to be participated in modulating pyroptosis. Hence, this study was aimed to elaborate the potential and mechanism of lactylation in myocardial I/R damage. We established the cell model of I/R through inducing hypoxia/reoxygenation (H/R) of H9c2 cells. It was uncovered that H/R stimulation drove cardiomyocyte pyroptosis and upregulated total lactylation level. Further, we demonstrated that promoting lactylation contributed to H/R-evoked pyroptosis, whereas silencing LDHA led to the opposite results. More than that, LDHA was confirmed to facilitate lactylation of NLRP3 at K245 site and increase its protein stability. Our findings indicated that activation of NLRP3 abolished the function of LDHA deficiency in H/R-treated H9c2 cells. In concert with the aforementioned outcomes, knockout of LDHA attenuated the infarct size and myocardial damage in I/R mice and upregulation of NLRP3 counteracted the effects of LDHA knockout on I/R-evoked injury in vivo. To summarize, the current research provided persuasive evidence that LDHA promoted myocardial I/R damage via enhancing NLRP3 lactylation to induce cardiomyocyte pyroptosis.