Abstract 15626: Epigenetic Modifications via Histone Acetylation by p300 Are Changed During the Transition From Cardiac Hypertrophy to Heart Failure
Background: An intrinsic histone acetyltransferase (HAT), p300, is required for acetylation and the transcriptional activity of GATA4, as well as pathological left ventricular hypertrophy (LVH) and the development of heart failure (HF) in vivo. Although most previously studied histone modifications are within the flexible tails of histones, H3K122 is reportedly a novel site of the histone globular domain acetylated by p300, and its acetylation activates gene transcriptions by destabilizing histone-DNA binding and increasing the accessibility of transactional factors to DNA. However, little is known about the extent histone modifications directly affect LVH and HF.
Hypothesis: We hypothesized that p300 could induce epigenetic changes by acetylation of the globular domain as well as tail domain of histone during the development of LVH and HF.
Methods and Results: Cultured rat neonatal primary cardiomyocytes were stimulated with phenylephrine (PE). Western blotting indicated that treatment with PE increased the acetylation of H3K122 as well as those of H3K9 and H3K14 in the tail domain of histones in cardiomyocytes. Peaks of acetylation of these domains were 4 hours after PE stimulation. These acetylations were significantly inhibited by p300 knockdown by siRNA or treatment with curcumin, a p300-specific HAT inhibitor. Conversely, p300 overexpression enhanced these acetylations. Chromatin-immunoprecipitation (ChIP) assays demonstrated that PE increased the recruitment of acetylated H3K122 and H3K9 onto ANF and BNP promoters containing the GATA element. To investigate the role of p300 HAT activity in histone acetylation in vivo, we utilized mice overexpressing p300 in the heart, which induced LVH. In vivo ChIP assays indicated that p300 overexpression increased recruitment of acetylated H3K122 and H3K9 onto ANF and BNP promoters containing the GATA element. Moreover, in vivo ChIP assays reviled that acetylation of H3K9 was increased around ANF and BNP promoters at the LVH stage but that of H3K122 was increased at the HF stage in hypertensive heart disease model of Dahl salt-sensitive rats
Conclusion: Our data indicate that acetylation of globular domains of histone by p300 is the key event of the transition from LVH to HF.
Author Disclosures: M. Funamoto: None. Y. Sunagawa: None. Y. Katanasaka: None. K. Shimizu: None. H. Wada: None. K. Hasegawa: None. T. Morimoto: None.
- © 2016 by American Heart Association, Inc.