The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice

Kana Shimizu,Nurmila Sari,Yusuke Miyazaki,Yoichi Sunagawa,Yasufumi Katanasaka,Hiroki Wakabayashi,Ayumi Katayama,Mai Genpei,Hiroyuki Shibata,Koji Hasegawa,Yoshiharu Iwabuchi,Masafumi Funamoto,Hideaki Kakeya,Tatsuya Morimoto,Satoshi Shimizu,Hiromichi Wada

doi:10.1038/s41598-020-64207-w

Abstract

Curcumin is a naturally occurring p300-histone acetyltransferase (p300-HAT) inhibitor that suppresses cardiomyocyte hypertrophy and the development of heart failure in experimental animal models. To enhance the therapeutic potential of curcumin against heart failure, we produced a series of synthetic curcumin analogues and investigated their inhibitory activity against p300-HAT. The compound with the strongest activity was further evaluated to determine its effects on cardiomyocyte hypertrophy and pressure overload-induced heart failure in mice. We synthesised five synthetic curcumin analogues and found that a compound we have named GO-Y030 most strongly inhibited p300-HAT activity. Furthermore, 1 μM GO-Y030, in a manner equivalent to 10 µM curcumin, suppressed phenylephrine-induced hypertrophic responses in cultured cardiomyocytes. In mice undergoing transverse aortic constriction surgery, administration of GO-Y030 at a mere 1% of an equivalently-effective dose of curcumin significantly attenuated cardiac hypertrophy and systolic dysfunction. In addition, this low dose of GO-Y030 almost completely blocked histone H3K9 acetylation and eliminated left ventricular fibrosis. A low dose of the synthetic curcumin analogue GO-Y030 effectively inhibits p300-HAT activity and markedly suppresses the development of heart failure in mice.

Highlights

All types of heart disease lead to the development of heart failure, which is a leading cause of death worldwide
We previously found both that curcumin suppresses cardiomyocyte hypertrophy by inhibiting the acetylation of GATA4 and histones, and that the oral administration of curcumin at a dose of 50 mg/kg prevents the development of heart failure in rat models of hypertension and myocardial infarction[12,13]
The results showed that GO-Y022 had approximately the same degree of activity as curcumin (Fig. 2a,b)

Summary

Introduction

All types of heart disease lead to the development of heart failure, which is a leading cause of death worldwide. When transgenic mice overexpressing mutant p300 that lacks HAT activity in the heart undergo the surgery, their degree of LV remodelling is similar to that of the wild-type mice[7] These findings indicate that the HAT activity of p300 plays a key role in LV remodelling and systolic dysfunction, suggesting that this activity may be a target for heart failure treatment. Balasubramanyam et al reported that curcumin inhibits p300-specific HAT activity[11] We previously found both that curcumin suppresses cardiomyocyte hypertrophy by inhibiting the acetylation of GATA4 and histones, and that the oral administration of curcumin at a dose of 50 mg/kg prevents the development of heart failure in rat models of hypertension and myocardial infarction[12,13]. We investigated the inhibitory effect of five curcumin analogues on p300-HAT activity and found that GO-Y030 ((1E,4E)-1,5-bis[3,5-bis(methoxymethoxy) phenyl]-1,4-pentadiene-3-one) inhibits p300-HAT activity and the development of heart failure in mice much more strongly than does curcumin

Methods

Results

Conclusion