Abstract 1510: Curcumin, a Natural p300-specific Histone Acetyltransferase Inhibitor, Prevents the Development Heart Failure in rats
Background: Signals activated by hemodynamic overload to the heart finally reach the nuclei of cardiac myocytes, activate hypertrophy-responsive transcription factors such as a zinc finger protein GATA4, and cause their maladaptive hypertrophy. Activation of these factors is mediated, in part, through acetylation controlled by histone deacetylases and an intrinsic histone acetyltransferase (HAT), p300. While nuclear acetylation is being recognized as a critical event during myocardial cell hypertrophy, pharmacological heart failure (HF) therapy that targets this pathway has yet to be established. The goal of this study was to determine whether a natural compound, curcumin, which possesses p300 HAT inhibitory action, can be used as a therapeutic agent for HF.
Methods: We utilized 2 different models of HF in vivo:
We randomized 11-week-old salt-sensitive Dahl (DS) rats (n=39) with compensated concentric hypertrophy by hypertension to oral chronic daily treatment with either curcumin (50 mg/kg/day) or a vehicle for 7 weeks.
One week after coronary ligation, 29 rats with moderate myocardial infarction (MI) were randomly assigned to treatment with curcumin or the vehicle for 6 weeks.
Results: There were no differences between curcumin and vehicle groups in all data examined before treatment. After treatment, echocardiography demonstrated that LV fractional shortening was significantly higher in curcumin groups than vehicle groups in both DS rats (curcumin: 48%, vehicle: 31%, p<0.05) and MI rats (curcumin: 30%, vehicle: 15%, p<0.0001). In both models, curcumin significantly decreased LV wall thickness and myocardial cell diameter. Compatible with these data, curcumin inhibited increases in LV BNP mRNA levels and plasma BNP levels in DS rats. Immunoprecipitation/Western blotting showed that the acetylated form of GATA4 and the p300/GATA4 complex in the heart markedly increased in DS rats compared with normotensive control rats. Curcumin inhibited GATA4 acetylation and disrupted the p300/GATA4 complex.
Conclusions: A natural compound, curcumin, partially prevents the development of HF in vivo, by inhibiting p300 HAT activiity. Thus, this non-toxic dietary compound will provide a novel therapeutic strategy for HF in humans.