Abstract 3817: A Natural p300-specific Histone Acetyltransferase Inhibitor, Curcumin, Exerts Synergistic Effects With Ace Inhibitor During Systolic Function Restoration After Myocardial Infarction in Rats
Purpose: 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. Recently, we found that curcumin (Cur), a p300 histone acetyltransferase inhibitor, prevents deterioration of the systolic function in two independent models of rat HF caused by myocardial infarction and hypertension. To clinically apply this novel therapy to humans, it should be clarified whether or not Cur exhibits additional effects on conventional HF therapy involving angiotensin-converting enzyme inhibitors (ACEI). Thus, we examined the effect of ACEI/Cur combination therapy on HF after myocardial infarction (MI).
Methods: Rats were subjected to a sham operation or MI. One week later, we performed left ventricular (LV) functional studies by employing echocardiography in all surviving rats. The rats with a moderate size of MI (fractional shortening (FS) <40%) were then randomly assigned to 4 groups:
solvents (control) (n=8),
enalapril (ACEI, 10 mg/kg/day) alone (n=8),
Cur (50 mg/kg/day) alone (n=8), and
Cur plus enalapril (n=8).
Oral treatments with these agents were repeated everyday and continued for 6 weeks.
Results: There were no differences among the 4 groups in any LV geometric and functional data examined before treatment. ACEI, but not Cur treatment, decreased the blood pressure in post-MI rats. After treatment, LVFS was significantly (p<0.05) higher in the ACEI (29%) and Cur (29%) groups than in the vehicle group (22%). Notably, LVFS significantly (p<0.05) increased on ACEI/Cur combination therapy (35%) compared with therapy involving either ACEI or Cur alone. The LV wall thickness and cardiomyocyte diameter were significantly smaller in the ACEI/Cur than the ACEI group. Moreover, perivascular fibrosis was significantly reduced in the ACEI and Cur groups compared with the vehicle group. This reduction was further augmented by the ACEI/Curombination therapy.
Conclusions: A p300 histone acetyltransferase inhibitor, Cur, restores the post-MI LV systolic function in rats without affecting the blood pressure. This natural non-toxic dietary compound in addition to ACEI exerts beneficial effects on LV systolic function.
This research has received full or partial funding support from the American Heart Association, National Center.