Author + information
- Kana Shimizu1,
- Yoichi Sunagawa1,2,3,
- Masafumi Funamoto1,2,
- Yasufumi Katanasaka1,2,3,
- Hiroyuki Shibata4,
- Hiromichi Wada2,
- Koji Hasegawa2 and
- Tatsuya Morimoto1,2,3
- 1Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
- 2Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan
- 3Shizuoka General Hospital, Shizuoka, Japan
- 4Department of Clinical Oncology, Graduate School of Medicine, Akita University, Akita, Japan
p300 histone acetyltransferase (HAT) activity was a key event on pathological cardiomyocyte hypertrophy and the development of heart failure in vivo. In our previous study, we reported that a natural p300-HAT inhibitor, curcumin, suppressed cardiomyocyte hypertrophy and the development of heart failure. Curcumin might be a therapeutic agent for heart failure therapy. A curcumin analogue, Y-030 [(1E, 4E-1,5-bis-(3,5(-bismethoxymethoxyphenyl)penta-1,4-dien-3-one], has a 30-fold higher potential to suppress tumor cell growth compared to curcumin. However, the effect of Y-030 on p300-HAT activity and hypertrophic responses has been unclear. We investigated whether curcumin analogue Y-030 suppresses p300-HAT activity in vitro and PE-induced hypertrophic responses in cardiomyocytes.
To determine the effect of Y-030 on p300-HAT activity, we performed in vitro HAT assay using recombinant p300 HAT domain. Neonatal rat cultured cardiomyocytes were treated with Y-030 or curcumin and stimulated with phenylephrine (PE). After 48 hours, we measured the ratio of acetylated histone H3, hypertrophic responses gene transcriptions, and cardiomyocyte surface area.
The result of in vitro HAT assay revealed that 0.6, 2 μM Y-030, but not 0.6, 2 μM curcumin, significantly inhibited p300-HAT activity in dose-dependent manner. In cardiomyocytes, PE-induced acetylation of histone H3K9 was suppressed by low dose of Y-030 (1, 3 μM) as well as 10 μM of curcumin. Low dose of Y-030 (1, 3 μM) also suppressed PE-induced hypertrophic response gene transcriptions such as ANF and β-MHC. Furthermore, Y-030 prevented PE-induced cardiomyocyte hypertrophy as well as curcumin.
Curcumin analogue, Y-030, effectively suppressed p300-HAT activity and hypertrophic responses. Thus, Y-030 might be a useful agent for heart failure therapy compared to curcumin.