Abstract Body: Background: Heart failure (HF) is a major cause of morbidity and mortality. Hereditary cardiomyopathies are the prototypic forms of HF. Notable among them is dilated cardiomyopathy (DCM) caused by mutations in the LMNA gene encoding Lamin A protein (LMNA-DCM). We have recently shown that KDM5A, a histone H3 lysine 4 demethylase, is activated in the hearts of human patients and mouse models of LMNA-DCM. Inhibition of the KDM5 family of proteins activates gene expression, including expression of genes involved in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) in iPSC-derived cardiomyocytes. Thus, we hypothesized that activation of the KDM5A in the LMNA-DCM is pathogenic and contributes to cardiac dysfunction.
Objective: The objective of this study is to determine the role of KDM5A in the pathogenesis of LMNA-DCM.
Methods and Results: The Lmna and Kdm5a genes were concomitantly deleted in the cardiac myocytes (CMs) in mice using cre recombinase. CM-specific deletion of the Lmna gene (Myh6-Cre:Lmna^F/F), representing a mouse model of LMNA-DCM, led to severe cardiac dysfunction, increased apoptosis, and premature death as published. The Myh6-Cre:Kdm5a^F/F mice showed no discernible phenotype. Deletion of the Kdm5a gene in CMs in the LMNA-DCM mice (Myh6-Cre:Lmna^F/F:Kdm5a^F/F) attenuated myocardial apoptosis, improved cardiac function, and prolonged survival. Specifically, left ventricular end-systolic and end-diastolic diameters (LVESD and LVEDD, respectively) were smaller and LV fractional shortening (LVFS) was greater in the Myh6-Cre: Lmna^F/F:Kdm5a^F/F mice as compared to the Myh6-Cre:Lmna^F/F mice. Likewise, the median and maximum survival times were increased by ~ 40 to 50% in the Myh6-Cre:Lmna^F/F:Kdm5a^F/F. Analysis of the CM transcripts by RNA-sequencing showed dysregulation of 6609 genes in the Myh6-Cre: Lmna^F/F CMs and 2791 genes were attenuated in the Myh6-Cre:Lmna^F/F:Kdm5a^F/F. Pathway analysis showed that genes involved in FAO and OXPHOS were the most suppressed in LMNA-DCM and were rescued upon Kdm5a deletion.
Conclusions: Deletion of the Kdm5a gene in the LMNA-DCM mice imparts salubrious effects by prolonging survival and improving cardiac dysfunction, and upregulating genes involved in OXPHOS and FAO. Thus, activation of KDM5A is likely pathogenic and contributes to the phenotypic expression of LMNA-DCM.