JMJD3 inhibition protects against isoproterenol-induced cardiac hypertrophy by suppressing β-MHC expression.

Abstract

Jumonji domain-containing protein D3 (JMJD3), a histone 3 lysine 27 (H3K27) demethylase, has been extensively studied for their participation in development, cellular physiology and a variety of diseases. However, its potential roles in cardiovascular system remain unknown. In this study, we found that JMJD3 played a pivotal role in the process of cardiac hypertrophy. JMJD3 expression was elevated by isoproterenol (ISO) stimuli both in vitro and in vivo. Overexpression of wild-type JMJD3, but not the demethylase-defective mutant, promoted cardiomyocyte hypertrophy, as implied by increased cardiomyocyte surface area and the expression of hypertrophy marker genes. In contrary, JMJD3 silencing or its inhibitor GSK-J4 suppressed ISO-induced cardiac hypertrophy. Mechanistically, JMJD3 was recruited to demethylate H3K27me3 at the promoter of β-MHC to promote its expression and cardiac hypertrophy. Thus, our results reveal that JMJD3 may be a key epigenetic regulator of β-MHC expression in cardiomyocytes and a potential therapeutic target for cardiac hypertrophy.