The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats.
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.
Morimoto
Tatsuya
T
Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
Sunagawa
Yoichi
Y
Kawamura
Teruhisa
T
Takaya
Tomohide
T
Wada
Hiromichi
H
Nagasawa
Atsushi
A
Komeda
Masashi
M
Fujita
Masatoshi
M
Shimatsu
Akira
A
Kita
Toru
T
Hasegawa
Koji
K
D000107:Acetylation; D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006333:Heart Failure / Q000517:prevention & control*; D006973:Hypertension / Q000150:complications; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D051381:Rats; D013599:Systole / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors*; D000099224:p300-CBP-Associated Factor
D003474:Curcumin; D004247:DNA; D004791:Enzyme Inhibitors; D050991:GATA4 Transcription Factor; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor