Nobiletin, a Polymethoxyflavonoid, Activates the Desuccinylase Activity of SIRT5 and Prevents the Development of Heart Failure

Sunagawa, Y.; Funamoto, M.; Hamabe-Horiike, T.; Hieda, K.; Yabuki, S.; Tomino, M.; Ikai, Y.; Suzuki, A.; Ogawahara, S.; Yabuta, A.; Sasaki, H.; Ebe, A.; Naito, S.; Takai, H.; Shimizu, K.; Shimizu, S.; Kawase, Y.; Naruta, R.; Katanasaka, Y.; Asakawa, T.; Kan, T.; Mori, K.; Murakami, A.; Ogura, M.; Inagaki, N.; Hasegawa, K.; Morimoto, T.

doi:10.1101/2024.01.16.575602

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bioRxiv · 10.1101/2024.01.16.575602

Nobiletin, a Polymethoxyflavonoid, Activates the Desuccinylase Activity of SIRT5 and Prevents the Development of Heart Failure

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Abstract

Nobiletin 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 SIRT5 in 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.

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Sunagawa, Y., Funamoto, M., Hamabe-Horiike, T., Hieda, K., Yabuki, S., Tomino, M., Ikai, Y., Suzuki, A., Ogawahara, S., Yabuta, A., Sasaki, H., Ebe, A., Naito, S., Takai, H., Shimizu, K., Shimizu, S., Kawase, Y., Naruta, R., Katanasaka, Y., Asakawa, T., Kan, T., Mori, K., Murakami, A., Ogura, M., Inagaki, N., Hasegawa, K., Morimoto, T.. 2024-01-16. Nobiletin, a Polymethoxyflavonoid, Activates the Desuccinylase Activity of SIRT5 and Prevents the Development of Heart Failure. https://doi.org/10.1101/2024.01.16.575602

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