Nobiletin Prevents Cardiac Hypertrophy via SIRT5-Mediated Downregulation of p300

BACKGROUND: Nobiletin is a natural compound useful for the prevention and treatment of several diseases. However, the precise role of nobiletin in the treatment of heart failure is unclear. In this study, we investigated the therapeutic potency of nobiletin and its functional mechanism. METHODS: The therapeutic potency of nobiletin for cardiac hypertrophy and systolic dysfunction was investigated using the transverse aortic constriction model in mice. To determine the target molecule of nobiletin in the heart, we purified and identified the binding proteins of biotinylated nobiletin by LC/MS-MS analysis. Male C57BL6j wild-type, SIRT5 (sirtuin 5) overexpressing transgenic mice and SIRT5 knockout mice were subjected to transverse aortic constriction or sham surgery. The succinylation site of p300 was identified by LC/MS-MS analysis. RESULTS: Nobiletin treatment prevents pressure overload-induced development of heart failure. Using affinity purification of biotinylated nobiletin from rat heart cell lysates, we identified SIRT5 as a novel nobiletin-binding protein. Nobiletin enhanced the desuccinylase activity of SIRT5 in vitro. SIRT5 levels were downregulated, and nuclear protein succinylation was upregulated in the failing heart. Compared with wild-type mice, SIRT5-overexpressing 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 activity of p300. The desuccinylated p300 mutant suppressed the phenylephrine-induced cardiomyocyte hypertrophic responses. CONCLUSIONS: These findings suggest that nobiletin prevents heart failure development through SIRT5-dependent inhibition of p300 acetyltransferase activity. Nobiletin, a nontoxic dietary compound, is a potential therapeutic agent for heart failure.