Abstract
The roles of the histone demethylase JMJD1C in cardiac hypertrophy remain unknown. JMJD1C was overexpressed in hypertrophic hearts of humans and mice, whereas the histone methylation was reduced. Jmjd1c knockdown repressed the angiotensin II (Ang II)-mediated increase in cardiomyocyte size and overexpression of hypertrophic genes in cardiomyocytes. By contrast, JMJD1C overexpression promoted the hypertrophic response of cardiomyocytes. Our further molecular mechanism study revealed that JMJD1C regulated AMP-dependent kinase (AMPK) in cardiomyocytes. JMJD1C did not influence LKB1 but repressed Camkk2 expression in cardiomyocytes. Inhibition of CAMKK2 with STO609 blocked the effects of JMJD1C on AMPK. AMPK knockdown blocked the inhibitory functions of JMJD1C knockdown on Ang II-induced hypertrophic response, whereas metformin reduced the functions of JMJD1C and repressed the hypertrophic response in cardiomyocytes.
Highlights
Cardiovascular disease has become the leading cause of death all around the world
We observed that the levels of H3K9me1, H3Kme2, and H3K9me3 were downregulated in hypertrophic cardiomyopathy (HCM) tissues, which was associated with the upregulation of JMJD1C (Figure 1C)
We observed the increase in methylation of H3K4 (H3K4me1 and H3K4me3) as well as acetylation of H3K9 in hypertrophic mouse hearts (Supplementary Figure 1). These findings demonstrated that JMJD1C was overexpressed in cardiac hypertrophy, which was associated with the downregulation of methylation of H3K9
Summary
Cardiovascular disease has become the leading cause of death all around the world. Cardiac hypertrophy is a pathological foundation of diverse cardiovascular diseases, including heart failure and hypertension (Veselka et al, 2017). The heart of mature mammals shows the low potential of cardiomyocyte proliferation. When the heart is injured and cardiomyocyte apoptosis occurs, the number of cardiomyocytes decreases (Nakamura and Sadoshima, 2018). The cardiomyocytes are unable to proliferate to support the increased demand of the heart. The cardiomyocytes undergo growth or hypertrophy to satisfy the demand. Pathological cardiac hypertrophy is a fundamental mechanism underlying diverse cardiovascular diseases, and sustained hypertrophy leads to arrhythmia and heart failure (Hou and Kang, 2012)
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