Histone lysine demethylase inhibition is a disease-modifying therapy for hypertrophic cardiomyopathy
Rationale: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterized by cardiac hypertrophy, fibrosis, arrhythmias, and sudden cardiac death (SCD). Although current therapies primarily target sarcomere dysfunction, the contribution of epigenetic dysregulation to HCM pathogenesis and its therapeutic potential remain poorly understood. Objective: To determine whether…
Hypertrophic cardiomyopathy (HCM) is a hereditary heart condition marked by thickening of the heart muscle, fibrosis, abnormal heart rhythms, and potentially fatal arrhythmias. Existing treatments mainly address the dysfunction of heart muscle fibers. However, the role of epigenetic abnormalities in HCM progression and their potential for treatment remains unclear.
A study investigated whether a compound called JIB-04, which inhibits histone lysine demethylases (KDMs), could slow or reverse HCM development. Experiments in mice with a mouse version of the human MYH7 R403Q mutation showed that JIB-04 stopped the progression of HCM, reduced muscle thickening and fibrosis, maintained normal heart function, and prevented sudden cardiac death triggered by the cyclosporin A drug.
Importantly, JIB-04 also reversed existing HCM, maintained its benefits when the drug was stopped, and improved heart function in older mice with spontaneous HCM.
By analyzing the overall gene activity and chromatin structure in mouse hearts, researchers found that JIB-04 partially restored the genes and chromatin patterns typically seen in HCM. They also identified a protein called PHF2 (also known as KDM7C) as a possible target of JIB-04 in both mouse and human HCM. When PHF2 was removed in experiments, hypertrophic, inflammatory, and fibrotic genes were turned off in heart cells, macrophages, and fibroblasts.
Human hearts with HCM showed higher levels of several KDMs that JIB-04 targets. In stem cell-derived heart muscle cells, JIB-04 corrected disease-related gene activity, returned a key heart protein called connexin-43 to its correct position on cell membranes, and boosted mitochondrial function. Prolonged use of JIB-04 did cause temporary liver enlargement and fat buildup, but using the antioxidant N-acetylcysteine along with JIB-04 prevented these liver issues without affecting the drug's effectiveness.
Overall, the findings suggest that targeting KDMs with JIB-04 can prevent and reverse HCM by reprogramming the heart's gene and chromatin activity. These results support the development of KDM-targeted therapies for HCM and provide new insights into the condition's underlying epigenetic mechanisms.
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