Inhibition of histone demethylase JMJD1C attenuates cardiac hypertrophy and fibrosis induced by angiotensin II

Abstract

Pathological cardiac hypertrophy is a major risk factor for cardiovascular morbidity and mortality. Histone demethylases (KDMs) are emerging regulators of transcriptional reprograming in cancer, however, their potential role in abnormal heart growth and fibrosis remains largely unknown. The aim of this current study was to examine the role of JMJD1C, an H3K9me2 specific demethylase, in angiotensin II (Ang II) induced cardiac hypertrophy and fibrosis. In this study, we observed that Ang II could increase the expression of JMJD1C detected by Western blot and RT-qPCR in vitro and in vivo. Immunofluorescence staining showed that the treatment of Ang II could increase cardiomyocyte size. RT-qPCR results have shown that Ang II could increase the expression of cell hypertrophic and fibrotic markers in H9c2 cells. Whereas, inhibition of JMJD1C by shRNA and JIB-04, a small molecule histone demethylase inhibitor, significantly reduced Ang II-induced cell hypertrophy, and hypertrophic and fibrotic marker overexpression. Furthermore, cardiomyocyte JMJD1C knockdown decreased Tissue Inhibitor of Metalloproteinases 1 (TIMP1) transcription with pro-fibrotic activity. In conclusion, JMJD1C plays an important role in Ang II-induced cardiac hypertrophy and fibrosis by activating TIMP1 transcription, targeting of JMJD1C may be an effective strategy for the treatment of Ang II-associated cardiac diseases.

Keywords: JMJD1C; TIMP1; angiotensin II; cardiac hypertrophy; epigenetic regulation; fibrosis.