Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Molecular Medicine

Background:

• Left ventricular hypertrophy (LVH) is a significant risk factor for cardiovascular disease.
• Pathological LVH involves transcriptional changes, including fetal gene reactivation and fibrosis.
• Histone lysine demethylases (KDMs) regulate gene transcription, but their role in cardiac hypertrophy and fibrosis is largely unknown.

Purpose of the Study:

• To investigate the role of the H3K9me2-specific demethylase Kdm3a in pressure overload-induced LVH and cardiac fibrosis.
• To evaluate the therapeutic potential of KDM inhibition for treating pathological cardiac remodeling.

Main Methods:

• Utilized gain and loss-of-function models of Kdm3a in the context of pressure overload.
• Administered a pan-KDM inhibitor, JIB-04, to assess its effects on LVH and fibrosis.
• Analyzed transcriptional changes in cardiomyocytes and cardiac tissue.

Main Results:

• Kdm3a gain-of-function promoted LVH and cardiac fibrosis.
• KDM3A specifically activated Timp1 transcription, contributing to pro-fibrotic activity.
• The pan-KDM inhibitor JIB-04 suppressed pressure overload-induced LVH and fibrosis.
• JIB-04 inhibited KDM3A and downregulated fibrotic gene expression.

Conclusions:

• KDM3A plays a pro-hypertrophic role in the heart and contributes to pathological fibrosis.
• Targeting KDMs pharmacologically presents a promising therapeutic approach for mitigating LVH and cardiac fibrosis.