Author:
Sunagawa Yoichi,Funamoto Masafumi,Hamabe-Horiike Toshihide,Hieda Kehima,Yabuki Seiichiro,Tomino Midori,Ikai Yoshimi,Suzuki Anna,Ogawahara Shintaro,Yabuta Asami,Sasaki Hana,Ebe Ayaka,Naito Shiomi,Takai Hidemichi,Shimizu Kana,Shimizu Satoshi,Kawase Yuto,Naruta Ryuya,Katanasaka Yasufumi,Asakawa Tomohiro,Kan Toshiyuki,Mori Kiyoshi,Murakami Akira,Ogura Masahito,Inagaki Nobuya,Hasegawa Koji,Morimoto Tatsuya
Abstract
AbstractNobiletin is a natural compound useful for the prevention and treatment of several diseases. However, the precise role of nobiletin in heart failure is unclear. Nobiletin treatment prevents pressure overload- and myocardial infarction-induced heart failure. Using affinity purification of biotinylated nobiletin from rat heart cell lysates, we identified sirtuin 5 (SIRT5) as a novel nobiletin-binding protein. Nobiletin enhanced the desuccinylase activity of SIRT5in vitro. Compared to wild-type mice, SIRT5-overexpressing transgenic mice resisted pressure overload-induced systolic dysfunction. Conversely, SIRT5 knockout disrupted the nobiletin-mediated therapeutic effects on heart failure in mice. SIRT5 desuccinylated p300 at lysine 1568 and reduced the histone acetyltransferase (HAT) activity of p300. The desuccinylated p300 mutant suppressed the phenylephrine-induced cardiomyocyte hypertrophic responses. These findings suggest that nobiletin prevents heart failure development through SIRT5-dependent inhibition of p300-HAT activity. Nobiletin, a nontoxic dietary compound, is a potential therapeutic agent for heart failure in humans.
Publisher
Cold Spring Harbor Laboratory