The Curcumin Analogue Go-Y030 Effectively Suppresses Cardiac Hypertrophy And Systolic Dysfunction Through P300-Hat Inhibition

Introduction: We previously found that a natural p300 histone acetyltransferase (HAT) inhibitor, curcumin, suppresses the development of heart failure. However, curcumin has low bioavailability; therefore, it is important to find analogues to it to enhance its therapeutic potential. In the present study, we focused on C 5 -curcuminoids, which possess stronger anti-cancer activity than curcumin, and investigated whether they inhibit p300-HAT activity, and therefore whether they may be useful as therapeutic agents for heart failure. Methods & Results: First, an in vitro p300 HAT assay revealed that the IC 50 value of GO-Y030, one of the C 5 -curcumin analogues investigated, was 1.1 μM, while that of curcumin was 9.4 μM. Moreover, the assay revealed that both mono-ketone moiety and 4 alkoxy groups (3, 3’, 5, 5’) were important for the enhancement of p300-HAT inhibition of GO-Y030. Second, cultured cardiomyocytes were treated with GO-Y030 or curcumin and then stimulated with phenylephrine (PE). 1 μM of GO-Y030 suppressed the following effects to the same extent as 10 μM of curcumin: PE-induced histone H3K9 acetylation, increases in the mRNA levels of ANF and BNP, and an increase in the surface area of cardiomyocytes. Third, C57BL/6j male mice were subjected to transverse aortic constriction (TAC) or sham operation. One day after the operation, TAC mice were randomly assigned to five groups: vehicle, 1 or 50 mg/kg curcumin, and 0.1 or 0.5 mg/kg GO-Y030. Oral administrations were repeated for 6 weeks. Echocardiographic analysis showed that 0.5 mg/kg GO-Y030 prevented a TAC-induced increase in posterior wall thickness and systolic dysfunction to the same extent as 50 mg/kg curcumin. Moreover, 0.5 mg/kg GO-Y030 suppressed increases in HW/BW ratio, myocardial cell diameter, perivascular fibrosis, mRNA levels of ANF and BNP, and histone H3K9 acetylation to the same extent as 50 mg/kg curcumin. Conclusions: These results indicate that the curcumin analog GO-Y030 strongly inhibits p300-HAT activity compared to curcumin and its derivatives in vitro , and that a low dose of GO-Y030 prevented both cardiomyocyte hypertrophy and the development of heart failure. These findings suggest that GO-Y030 may be more effective than curcumin for heart failure therapy.