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

• Published in: Scientific reports Vol. 10; no. 1; p. 7172
• Main Authors: Shimizu, Kana, Sunagawa, Yoichi, Funamoto, Masafumi, Wakabayashi, Hiroki, Genpei, Mai, Miyazaki, Yusuke, Katanasaka, Yasufumi, Sari, Nurmila, Shimizu, Satoshi, Katayama, Ayumi, Shibata, Hiroyuki, Iwabuchi, Yoshiharu, Kakeya, Hideaki, Wada, Hiromichi, Hasegawa, Koji, Morimoto, Tatsuya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.04.2020; Nature Publishing Group
• Subjects: 13/95; 45/90; 631/337/458/1275; 64/60; 692/4019/592/1540; 82/29; 96/34; Acetylation; Animal models; Animals; Aorta; Cardiomegaly - drug therapy; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomyocytes; Congestive heart failure; Curcumin; Curcumin - analogs & derivatives; Curcumin - chemical synthesis; Curcumin - chemistry; Curcumin - pharmacology; Event-related potentials; Fibrosis; Heart failure; Heart Failure - drug therapy; Heart Failure - metabolism; Heart Failure - pathology; Histone acetyltransferase; Humanities and Social Sciences; Hypertrophy; Male; Mice; multidisciplinary; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phenylephrine; Pressure; Rats; Rats, Sprague-Dawley; Science; Science (multidisciplinary); Surgery; Ventricle
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-64207-w

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.