5-Demethylnobiletin Ameliorates Isoproterenol-Induced Cardiac Fibrosis and Apoptosis by Repressing the Sirt1/FOXO3a/NF-κB and Wnt/β-Catenin Pathways.

Apoptosis and fibrosis are two main factors leading to heart failure. 5-Demethylnobiletin (5-OH-Nob) is a natural polymethoxyflavone derived from the peel of citrus fruits that has many biological effects, such as antioxidative stress and anti-inflammatory effects. Here, we aimed to probe the function and mechanism of 5-OH-Nob in myocardial damage. Primary rat cardiac fibroblasts were exposed to isoproterenol (ISO, 10 µM) to establish an in vitro model of cardiac damage, and ISO (30 mg/kg/d) was used to induce myocardial fibrosis in mice. 5-OH-Nob was used for treatment in vivo and ex vivo. Functional assays revealed that 5-OH-Nob alleviated the apoptosis and fibrosis of cardiac fibroblasts treated with ISO and increased cell viability (p < 0.05). In vivo, 5-OH-Nob treatment ameliorated cardiac injury in ISO-treated mice (p < 0.05). Mechanistically, 5-OH-Nob treatment enhanced Sirt1 expression and suppressed ISO-mediated activation of the FOXO3a/nuclear transcription factor-κB (NF-κB) and Wnt/β-catenin pathways. Furthermore, Sirt1 inhibition attenuated the protective effect of 5-OH-Nob on ISO-induced cardiac apoptosis and fibrosis. Overall, 5-demethylnobiletin mediates the Sirt1/FOXO3a/NF-κB and Wnt/β-catenin pathways to mitigate ISO-induced myocardial fibrosis and apoptosis.