JMJD6 inhibits NF-κB Activation by Demethylating R149 of p65 Subunit to Attenuate Isoproterenol-Induced Cardiac Hypertrophy

Abstract

Histone modification plays an important role in pathological cardiac hypertrophy and heart failure. However, the mechanisms underlying pathological cardiac hypertrophy still remain to be elucidated, especially involving histone arginine demethylation. Here, we investigated the roles of histone arginine demethylase jumonji domain-containing protein 6 (JMJD6) in isoproterenol (ISO)-induced pathological cardiac hypertrophy. JMJD6 level was upregulated in hypertrophic and ejection fraction preserved heart failure (EFpHF) rat cardiac tissues, while it was decreased in ejection fraction reduced heart failure (EFrHF) patients. JMJD6 overexpression attenuated ISO-induced cardiac hypertrophy as reflecting by the reduction of cardiomyocyte surface area and hypertrophic genes expression in cardiomyocytes. Meanwhile, cardiac-specific JMJD6 overexpression protected the hearts against ISO-induced cardiac hypertrophy, fibrosis, and rescued cardiac function. Conversely, depletion of JMJD6 by single-guide RNA (sgRNA) promoted ISO-induced hypertrophic responses in cardiomyocytes. We further demonstrated that JMJD6 interacts with nuclear factor kappa B (NF-κB) p65 in cytoplasm and reduces the nucleus level of p65 under hypertrophic stimulation in vivo and in vitro. Mechanistically, JMJD6 binds to p65 and demethylate p65 at arginine (R) 149 to inhibit the nuclear translocation of p65, and then inactivated NF-κB signaling, thereby protecting against pathological cardiac hypertrophy. We also found that JMJD6 demethylates histone H3R8, which may a new histone substrate of JMJD6. These findings indicate that JMJD6 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.