Multi-omics analysis of early reperfused ischemic heart reveals ERRß/? activation protects against acute myocardial infarction injury [CUT&Tag]

In the present study, the induction of AMI in rats was achieved by ligating the left anterior descending coronary artery (LAD) for a duration of one hour (early time reperfusion, defined as ETR) or six hours (late time reperfusion, and defined as LTR), followed by reperfusion. Sham-operated rats served as controls for the experiment. Bulk tissue transcriptomic sequencing, metabolomic profiling, and single-nucleus RNA sequencing were performed to analyze the transcriptome and metabolome of the ischemic hearts. TF motif analysis was used to predict the potential transcriptional factor. In addition, we investigated the role of ERRß and ERR? in vitro using neonatal rat ventricular myocytes (NRVMs) subjected to hypoxia/reoxygenation (H/R). We administered the ERRß/? agonist GSK4716 to rats to assess its therapeutic effects on AMI injury, and compared the protective mechanism with fenofibrate.Bulk tissue transcriptomic and metabolomic profiling demonstrated that the protective effect of ETR on AMI is mediated by two major parts of FAO and dedifferentiation. Single-nucleus RNA sequencing revealed four distinct cardiomyocyte subpopulations (CM1-CM4), and ETR attenuated AMI injury by preserving a greater number of sub-injured CM2 and immature-like CM4. In addition, ERRß/? was found to regulate the expression of FAO and immature cardiomyocyte signature genes in vivo and in vitro. Notably, pretreatment with the ERRß/? agonist GSK4716 significantly enhanced the protective effect of ETR on AMI by activating FAO and immature CM genes. CONCLUSIONS: The findings indicate that the protective effect of early time reperfusion is associated with preserved FAO and dedifferentiation. Activation of ERRß significantly enhances these protective effects, highlighting the therapeutic potential of ERRß activation in ameliorating AMI injury. These findings suggest that targeting the ERRß pathway may provide an effective strategy for the treatment of AMI. Overall design: CUT&Tag of ERRß in the cardiomyocytes collected from the sham rats.