Abstract 18911: Histone Acetylation Domain by p300 are Changed During the Transition From Cardiac Hypertrophy to Heart Failure

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Background: A histone acetyltransferase (HAT), p300, is required for acetylation and the transcriptional activity of GATA4, as well as for pathological left ventricular hypertrophy (LVH) and the development of heart failure (HF) in vivo. Most previously studied histone modifications have been carried out within histone tail domain, it has been recently reported that the H3K122 is a novel site of the histone globular domain acetylated by p300, and that its acetylation activates gene transcriptions by destabilizing histone-DNA binding. However, little is known about the extent to which histone modifications directly affect LVH and HF.

Hypothesis: We hypothesized that p300 induces epigenetic changes through the acetylation of both the globular domain and the 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 in cardiomyocytes. Peak of acetylation of H3K9 was 12 hours after PE stimulation but that of H3K122 was 36 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: These results indicate that the acetylation of H3K122 in the globular domain of histones by p300 is a key event of the transition from LVH to HF.

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