EZH2 is an epigenetic enzyme repressing a wide variety of gene expression by adding methyl groups on histone H3 lysine 27 residue. In myocardial infarction (MI), most of these targeted genes are related to metabolism.

This study aims to assess the benefit of GSK-343 (EZH2 inhibitor) on cardiac function and lipid metabolism in heart failure with reduced ejection fraction (HFrEF) induced by MI. We hypothesize that EZH2 modulates fatty acid (FA) cardiac metabolism and its inhibition minimizes lipid metabolism disruptions and improves cardiac function.

Female mice underwent MI by ligation of left anterior descending coronary artery and were treated daily with vehicle or GSK-343 (7 days). We evaluated cardiac function (echocardiography), cardiac gene expression profiling (RNA-seq, RT-qPCR) and the circulating lipidome was assessed (mass spectrometry-based untargeted lipidomics).

MI induced a reduction of EF from 46% (sham) to 18% (MI) while GSK-343 prevents this dysfunction (EF∼38%). RNA-seq analysis revealed wide gene expression changes in MI, changes normalized with GSK-343 treatment. The latter changes include, among the 561 down-regulated genes (FC 0.5 and 2; P=10-4), 16 mitochondrial DNA-encoded genes (e.g. mt-Nd1, Mt-Rnr1), 57 genes related to mitochondrial function (e.g. Ppargc1-alpha) and 15 to lipid metabolism (e.g. Ppar-alpha, Acadm). As expected, most of these metabolic gene expressions were validated using RT-qPCR and emphasized a rescue upon GSK-343 treatment. We observed a similar pattern for other metabolic genes such as Klf15, an Ezh2 putative direct target gene and a master metabolic gene regulator, Cpt2 encoding a FA transporter and Pnpla2 implicated in triglyceride (TG) metabolism. Because disruption in FA utilization affect the lipidome, we used an untargeted lipidomics approach to evaluate the global impact of MI±GSK-343. In plasma, while MI enhanced 18 TG (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. Finally, 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) while GSK-343 treatment abolished most of these correlations.

Our study suggests that inhibiting EZH2 is of therapeutic interest to normalize lipid metabolism perturbations and improve cardiac function in HFrEF induced by MI.