The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats
Tatsuya Morimoto, … , Toru Kita, Koji Hasegawa
Tatsuya Morimoto, … , Toru Kita, Koji Hasegawa
Published February 21, 2008
Citation Information: J Clin Invest. 2008;118(3):868-878. https://doi.org/10.1172/JCI33160.
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Research Article

The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats

Abstract

Hemodynamic overload in the heart can trigger maladaptive hypertrophy of cardiomyocytes. A key signaling event in this process is nuclear acetylation by histone deacetylases and p300, an intrinsic histone acetyltransferase (HAT). It has been previously shown that curcumin, a polyphenol responsible for the yellow color of the spice turmeric, possesses HAT inhibitory activity with specificity for the p300/CREB-binding protein. We found that curcumin inhibited the hypertrophy-induced acetylation and DNA-binding abilities of GATA4, a hypertrophy-responsive transcription factor, in rat cardiomyocytes. Curcumin also disrupted the p300/GATA4 complex and repressed agonist- and p300-induced hypertrophic responses in these cells. Both the acetylated form of GATA4 and the relative levels of the p300/GATA4 complex markedly increased in rat hypertensive hearts in vivo. The effects of curcumin were examined in vivo in 2 different heart failure models: hypertensive heart disease in salt-sensitive Dahl rats and surgically induced myocardial infarction in rats. In both models, curcumin prevented deterioration of systolic function and heart failure–induced increases in both myocardial wall thickness and diameter. From these results, we conclude that inhibition of p300 HAT activity by the nontoxic dietary compound curcumin may provide a novel therapeutic strategy for heart failure in humans.

Authors

Tatsuya Morimoto, Yoichi Sunagawa, Teruhisa Kawamura, Tomohide Takaya, Hiromichi Wada, Atsushi Nagasawa, Masashi Komeda, Masatoshi Fujita, Akira Shimatsu, Toru Kita, Koji Hasegawa

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Figure 1

Curcumin inhibits PE-induced hypertrophic responses in cardiomyocytes.

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Curcumin inhibits PE-induced hypertrophic responses in cardiomyocytes. (...
(A and B) Primary cardiomyocytes from neonatal rats were stimulated with saline or 30 μM PE in the presence of curcumin (10 μM in A and 5 or 10 μM in B) or a corresponding amount of its vehicle (DMSO) as a control for 48 hours. (A) These cells were subjected to immunocytochemistry using the primary antibody against cardiac MHC followed by staining with a secondary antibody conjugated with peroxidase (brown signals). Scale bar: 10 μm. (B) Myocardial cell-surface area was measured as described in Methods. Values in each group are mean ± SEM (μm) from 50 cells. (C and D) Cardiomyocytes were transfected with 0.5 μg of pANF-luc (C) or pβ-MHCluc (D) and 0.0025 μg of pRL-SV40. Then, these cells were stimulated with saline or 30 μM PE in the presence of curcumin or a corresponding amount of its vehicle for 48 hours. The relative promoter activities were calculated from the ratio of firefly Luc activity to sea pansy Luc activity. The data shown are mean ± SEM from 3 independent experiments, each carried out in duplicate.