Title:Dose-dependent Effects of PRC2 and HDAC Inhibitors on Cardiomyocyte
Hypertrophy Induced by Phenylephrine
Volume: 24
Issue: 4
Author(s): Zhenyi Zhao, Jian Lv, Ningning Guo, Qiuxiao Guo, Sai Zeng, Yu Fang, Weixin Chen*Zhihua Wang*
Affiliation:
- Department of Cardiology, Fuwai Hospital Chinese
Academy of Medical Sciences, Shenzhen, 518057, China
- Shenzhen Key Laboratory
of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, 518057, China
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
Keywords:
Cardiac hypertrophy, histone acetylation, histone methylation, HDAC, PRC2, epigenetic reprogramming.
Abstract:
Introduction: Postnatal cardiomyocytes respond to stress signals by hypertrophic
growth and fetal gene reprogramming, which involves epigenetic remodeling mediated by histone
methyltransferase polycomb repressive complex 2 (PRC2) and histone deacetylases (HDACs).
However, it remains unclear to what extent these histone modifiers contribute to the development
of cardiomyocyte hypertrophy.
Methods: Neonatal rat ventricular myocytes (NRVMs) were stimulated by phenylephrine (PE;
50μM) to induce hypertrophy in the presence or absence of the PRC2 inhibitor GSK126 or the
HDACs inhibitor Trichostatin A (TSA). Histone methylation and acetylation were measured by
Western blot. Cell size was determined by wheat germ agglutinin (WGA) staining. Cardiac hypertrophy
markers were quantified by quantitative reverse transcription polymerase chain reaction
(qRT-PCR).
Results: PE treatment induced the expression of cardiac hypertrophy markers, including natriuretic
peptide A (Nppa), natriuretic peptide B (Nppb), and myosin heavy chain 7 (Myh7), in a time-dependent
manner in NRVMs. Histone modifications, including H3K27me3, H3K9ac, and H3K27ac,
were dynamically altered after PE treatment. Treatment with TSA and GSK126 dose-dependently
repressed histone acetylation and methylation, respectively. While TSA reversed the PE-induced
cell size enlargement in a wide range of concentrations, cardiomyocyte hypertrophy was only inhibited
by GSK126 at a higher dose (1μM). Consistently, TSA dose-dependently suppressed the induction
of Nppa, Nppb, and Myh7/Myh6 ratio, while these indexes were only inhibited by
GSK126 at 1μM. However, TSA, but not GSK126, caused pro-hypertrophic expression of pathological
genes at the basal level.
Conclusion: Our data demonstrate diversified effects of TSA and GSK126 on PE-induced cardiomyocyte
hypertrophy, and shed light on epigenetic reprogramming in the pathogenesis of cardiac
hypertrophy.
