Crucumin, a natural p300-specific histone acetyltransferase inhibitor, is a therapeutic agent that prevents the development of heart failure in vivo

Crucumin, a natural p300-specific histone acetyltransferase inhibitor, is a therapeutic agent that prevents the development of heart failure in vivo

Tatsuya Morimoto1, Teruhisa Kawamura2, Tomohide Takaya2, Hiromichi Wada2, Yoichi Sunagawa2, Masaki Ikemoto3, Masatoshi Fujita3, Toru Kita1, Koji Hasegawa2.

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

第10回日本心不全学会学術集会 (東京), 2006/10/13 (ポスター).

Abstract

Purpose: One of intrinsic histone acetyltransferases, p300, serves as a coactivator of hypertrophy-responsive transcriptional factors such as a cardiac zinc finger protein GATA-4 and is involved in its hypertrophic stimulus-induced acetylation and DNA binding. Our purpose is to investigate whether a p300- HAT specific inhibitor, curcumin, represses the development of heart failure.

Methods and Results: First, we examined effects of curcumin on primary neonatal rat cardiac myocytes in culture. Curcumin (5-10 uM) repressed phenylephrine-induced hypertrophic responses such as increase in cell size and transactivation of the ANF and beta-MHC promoters. Curcumin also blocked phenylephrine-induced increase in acetylation and DNA binding activity of GATA-4 as well as acetylation of histones. Second, to determine whether curcumin can prevent the development of heart failure in vivo, we have utilized a salt-sensitive Dahl (DS) rat model of hypertension. In this model, left ventricular concentric hypertrophy at the age of 11 weeks is followed by decompensated heart failure at the age of 17 weeks. We randomized 11-week-old DS rats (n = 56) to oral chronic treatment with curcumin (50 mg/Kg/day) or vehicle. At the age of 17 weeks, curcumin significantly ameliorated the survival rate (curcumin: 76%, vehicle: 44%, p < 0.001).

Conclusion: A natural compound, curcumin represses hypertrophic responses in cardiac myocytes by perturbing a p300-dependent transcriptional pathway, and prevents the development of hypertension-induced decompensated heart failure in vivo.