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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE304090 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Analysis of the effects of aging on the development of dilated cardiomyopathy by characterizing both changes in ejection fraction (EF) and gene expression profile in 3 groups of male mice: Control (Cont or WT, n=11) and transgenic (Tg or KO) mice with either high EF (KO-H or Tg-H, n=7) or low EF (KO-L or Tg-L, n=6). We previously produced a line of transgenic mice (Tg) on a mixed genetic background where cardiac-specific overexpression of Cre recombinase reduced expression of the EP4 receptor gene. There were no obvious phenotypes in 10-12-week-old male Tg mice. To determine if a cardiac phenotype developed in aged mice, we assessed cardiac structure and function by echocardiography, histology and gene expression in 23-33-week-old male Tg and littermates (Cont). After echocardiography, hearts were removed to assess hypertrophy (MCSA), fibrosis (ICF) and macrophage infiltration by histological methods and for extraction of total RNA and protein. Cont mice had a normal EF of 80Â±0.6% (n=70), whereas Tg mice had a lower EF (60Â±2.7%, n=55, p<0.001) coupled with left ventricular dilatation. The distribution of EFs in the Tg mice was large, ranging from normal to below 30%. MCSA and infiltrating macrophages were not different between groups, but ICF increased by 35% in Tg mice. Cre protein levels in heart lysates did not correlate with either age or EF. In contrast to male Tg mice, female Tg mice had no cardiac dysfunction assessed by echocardiography from 12 to 28 weeks of age. To understand gene expression differences between Cont and Tg mice, whole genome gene expression profiling (Illumina BeadChips) on hearts of 30-32 week old male mice was done. Data indicated that 595 genes were overexpressed in the Tg hearts, 156 of which changed more than 2-fold, including genes involved in remodeling, inflammation, and oxidative stress. 512 genes were downregulated in the Cont hearts, 79 of which changed more than 2-fold, including genes involved with calcium handling, K+ channels, and fatty acid transport and metabolism. In conclusion, Cre overexpression and EP4 knock down in cardiac myocytes in aged male but not female Tg mice are in part associated with increased fibrosis, reduced EF and dilated cardiomyopathy; however, Cre protein itself does not seem to be responsible for the cardiomyopathy. The absence of cardiac dysfunction in female mice suggests a sexual dimorphism in the phenotype. Creation of the cardiac-myocyte specific EP4 KO mouse and littermate controls was described in JY Qian et al, Hypertension 2008: 51(pt 2):560-566. Total RNA extracted from left ventricle of control (Cont or WT, n =11) and cardiac-specific EP4 KO (Tg or KO, n=13) male mice (mean age 31 weeks).

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

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