Curcumin, a natural p300-specific HAT inhibitor, represses hypertrophic responses in cardiac myocytes

Curcumin, a natural p300-specific HAT inhibitor, represses hypertrophic responses in cardiac myocytes

Yoichi Sunagawa1, Teruhisa Kawamura1, Tomohide Takaya1, Hiromichi Wada1, Akira Shimatsu1, Koji Hasegawa1, Tatsuya Morimoto2, Toru Kita2, Masatoshi Fujita3.

  1. Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
  2. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  3. School of Health Sciences, Faculty of Medicine, Kyoto University, Kyoto, Japan.

The 1st International Congress of Cardiomyopathies and Heart Failure (Kyoto, Japan), 2007/03/12 (Poster).

Abstract

Background: Hypertrophic stimuli activate cardiac transcription factors such as SRF, MEF-2 and a zinc finger protein GATA-4 and modulate gene expression in cardiac myocytes. These changes finally lead to the development of heart failure in vivo. Acetylation is one of critical mechanisms that activate these transcriptional factors, and mediated, in part, by an intrinsic histone acetyltransferase (HAT) such as a transcriptional coactivator p300. However, a pharmacological heart failure therapy that targets this pathway has not been established. One of compounds that have been reported to inhibit p300 HAT activity is a natrual compound, curcumin, a major curcumanoid in the spice turmeric isolated from Curcuma longa. This compound inhibits histone acetylation in vitro and represses p300-mediated chromatin transcription in cultured HeLa cells.

Methods and Results: We examined effects of curcumin on primary cardiac myocytes from neonatal rats in culture. We show here that curcumin (5-10 uM) repressed phenylephrine-induced hypertrophic responses such as myofibrilar organization and increase in cell size. The same concentrations of this compound did not affect saline-stimulated myocytes, excluding the possibility of their toxic effects. Transient transfection experiments revealed that curcumin significantly inhibits phenylephrine-induced transactivation of the atrial natriuretic factor and beta-myosin heavy chain promoters. Curcumin also blocked phenylephrine-induced increase in acetylation and DNA binding activity of GATA-4 as well as acetylation of histones.

Conclusion: A natrual compound, curcumin represses hypertrophic responses in cardiac myocytes, in part, by perturbing a p300-dependent transcriptional pathway. Application of this compound to the treatment of heart failure would be expected.