Abstract
The histone demethylase JMJD family is involved in various physiological and pathological functions. However, the roles of JMJD1A in the cardiovascular system remain unknown. Here, we studied the function of JMJD1A in cardiac hypertrophy. The mRNA and protein levels of JMJD1A were significantly downregulated in the hearts of human patients with hypertrophic cardiomyopathy and the hearts of C57BL/6 mice underwent cardiac hypertrophy induced by transverse aortic constriction (TAC) surgery or isoproterenol (ISO) infusion. In neonatal rat cardiomyocytes (NRCMs), siRNA-mediated JMJD1A knockdown facilitated ISO or angiotensin II-induced increase in cardiomyocyte size, protein synthesis, and expression of hypertrophic fetal genes, including atrial natriuretic peptide (Anp), brain natriuretic peptide (Bnp), and Myh7. By contrast, overexpression of JMJD1A with adenovirus repressed the development of ISO-induced cardiomyocyte hypertrophy. We observed that JMJD1A reduced the production of total cellular and mitochondrial levels of reactive oxygen species (ROS), which was critically involved in the effects of JMJD1A because either N-acetylcysteine or MitoTEMPO treatment blocked the effects of JMJD1A deficiency on cardiomyocyte hypertrophy. Mechanism study demonstrated that JMJD1A promoted the expression and activity of Catalase under basal condition or oxidative stress. siRNA-mediated loss of Catalase blocked the protection of JMJD1A overexpression against ISO-induced cardiomyocyte hypertrophy. These findings demonstrated that JMJD1A loss promoted cardiomyocyte hypertrophy in a Catalase and ROS-dependent manner.
Highlights
Epigenetic regulation and posttranslational regulation of histone and nonhistone proteins are critically involved in the development of cardiac hypertrophy [1,2,3]
JMJD1A Expression Is Reduced during Cardiac Hypertrophy
We tested the expression of Jmjd1a mRNA and protein levels and found that either the mRNA or protein level of Jmjd1a was significantly downregulated in transverse aortic constriction (TAC)-induced hypertrophic hearts (Figures 1(e) and 1(f)), which was accomplished with the increase in H3K9me1 and H3K9me2 (Figure 1(f))
Summary
Epigenetic regulation and posttranslational regulation of histone and nonhistone proteins are critically involved in the development of cardiac hypertrophy [1,2,3]. The histone deacetylases essentially participate in the development of cardiac hypertrophy by regulating the metabolism, mitochondrial homeostasis, and gene transcription [4,5,6,7,8]. In comparison to histone acetylation, the roles of histone methylation enzymes in cardiac hypertrophy are largely unknown. Lysine methylation is one of the most prominent histone posttranslational modifications that regulate chromatin structure and gene expression. Recent studies have implicated the roles of histone methylation/demethylation in cardiac hypertrophy and fibrosis [10, 11]
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