TY - JOUR
T1 - The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice
AU - Shimizu, Kana
AU - Sunagawa, Yoichi
AU - Funamoto, Masafumi
AU - Wakabayashi, Hiroki
AU - Genpei, Mai
AU - Miyazaki, Yusuke
AU - Katanasaka, Yasufumi
AU - Sari, Nurmila
AU - Shimizu, Satoshi
AU - Katayama, Ayumi
AU - Shibata, Hiroyuki
AU - Iwabuchi, Yoshiharu
AU - Kakeya, Hideaki
AU - Wada, Hiromichi
AU - Hasegawa, Koji
AU - Morimoto, Tatsuya
N1 - Funding Information:
The authors would like to thank Mr. Philip Hawke of the University of Shizuoka Scientific English Program for his comments on the English in the manuscript. This work was supported in part by grants from the Japan Science and Technology Agency [26460071, T. Morimoto; 15K21279, Y. Sunagawa; 16K18876, Y. Katanasaka; and 15K09108, K. Hasegawa] and the Japan Society for the Promotion of Sciences [LS061, H. Kakeya].
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-020-64207-w
DO - 10.1038/s41598-020-64207-w
M3 - Article
C2 - 32346115
AN - SCOPUS:85084002859
VL - 10
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 7172
ER -