Pharmacological inhibition of the epigenetic enzyme EZH2 attenuates cardiac dysfunction and mitigates lipid metabolism perturbations in a murine model of myocardial infarction

Rational: EZH2, an epigenetic enzyme, acts as a transcriptional repressor for genes dysregulated after myocardial infarction (MI). Objective: This study aims to assess the benefits of GSK-343 (EZH2 inhibitor) on cardiac function and lipid metabolism after MI. Methods: Mice were treated daily with vehicle or GSK-343 for 7 days after MI and we evaluated cardiac function (echocardiography), gene expression profiling (RNA-seq) and circulating lipidome (untargeted lipidomics). Results: The 28% MI decreased ejection fraction (EF) was improved by 20% with GSK-343. RNA-seq analysis revealed wide changes in MI normalized with GSK-343: 16 mitochondrial DNA-encoded genes, 57 genes related to mitochondrial function and 15 to lipid metabolism among the 561 down-regulated genes (FC 0.5 and 2; p=10-4). In plasma, while MI enhanced 18 triglycerides (1.24-2.43-fold; p<0.05) and decreased 32 choline glycerophospholipids (PC; 0.55-0.81-fold, p<0.05), GSK-343 normalized these perturbations. In MI, some of these lipids positively correlated with EF (e.g. PC40:6; R=0.84, p=0.004) or with cardiac hypertrophy (e.g. DG18:1_18:2; R=0.81, p=0.007) and GSK-343 abolished most of these correlations. Conclusion: Our study suggests that inhibiting EZH2 is of therapeutic interest to normalize lipid metabolism perturbations and improve cardiac function after MI. Overall design: total RNA isolated from left ventricles of 5 independent sham or MI mice previously treated either with GSK-343 (20 mg/kg, Interchim Cat# XLR94D) or vehicle (20% captisol), 8 days post-MI, Poly-A mRNA-seq, sequencing length of 150 nt paired end (PE150) with the Illumina NovaSeq 6000 was performed.