Tristetraprolin Regulates Metabolic And Epigenetic Remodeling In Cardiomyocytes Post Myocardial Infarction

Myocardial infarction (MI) triggers profound remodeling in the infarcted, border (BZ), and remote zones of the myocardium. Here, we studied the metabolic remodeling and epigenetic modifications that occur in response to inflammation in the BZ, focusing the role of an mRNA-binding protein that causes degradation of its target mRNA molecules, tristetraprolin (TTP). Inflammatory cells were observed to increase in the BZ, associated with the release of IL-1B and IFN-γ. Among proteins that are altered in the BZ cardiomyocytes, TTP displayed a significant increase in its mRNA and protein levels in the BZ. Isotope tracing using U-13C6 glucose in TTP-overexpressing cells showed that TTP overexpression results in an increase in TCA metabolites upstream of alpha ketoglutarate dehydrogenase (αKGDH), and a decrease of downstream metabolites, suggesting blocked activity at the level of αKGDH. We then identified the mRNA of the E2 component of αKGDH, Dihydrolipoamide S-Succinyltransferase (DLST), to be a target of TTP. Consistent with these findings, DLST mRNA and protein levels are decreased in BZ. DLST needs to be lipoylated to become active, and our data indicate that the mRNA for a key enzyme in DLST lipoylation (lipoic acid synthase, LIAS) is also a target of TTP. Overexpression of TTP led to a decrease in the level of DLST lipoylation. Epigenetic studies showed that, overexpression of TTP resulted in significant decrease in acetylation and methylation of H4K20. Finally, we demonstrated that heart specific TTP KO mice are protected against ischemic injury compared to WT mice, indicating that deletion of TTP alters the remodeling of the BZ, through its role in the regulation of αKGDH and production of αKG in response to infiltration of inflammatory cells.