Screening of an FDA-approved compound library identifies apigenin for the treatment of myocardial injury

Abstract

Apigenin is the active ingredient in Ludangshen. Although previous studies reported the cardioprotective actions of apigenin against doxorubicin (Dox)-induced cardiomyopathy, the underlying mechanisms remain incompletely understood. Since apigenin beneficially regulates various aspects of mitochondrial function and dynamics, we asked whether apigenin improves heart function in mice with Dox-induced cardiomyopathy by regulating the mitochondrial unfolded protein response (UPR mt ). Co-administration of apigenin significantly restored heart function, reduced myocardial swelling, inhibited cardiac inflammation, increased cardiac transcription of UPR mt -related genes, and promoted cardiomyocyte survival in Dox-treated mice. In turn, blockade of UPR mt abolished the mito-and cytoprotective effects of apigenin, evidenced by decreased ATP production, suppressed mitochondrial antioxidant capacity, and increased apoptosis, in Dox-treated, cultured HL-1 cardiomyocytes. Furthermore, apigenin treatment prevented Dox-induced downregulation of Sirt1 and Atf5 expression, and the beneficial effects of apigenin were completely nullified in Sirt1 knockout (KO) mice or after siRNA-mediated Sirt1 knockdown in vitro. We thus provide novel evidence for a promotive effect of apigenin on UPR mt via regulation of the Sirt1/Atf5 pathway. Our findings uncover that apigenin seems to be an effective therapeutic agent to alleviate Dox-mediated cardiotoxicity.

Apigenin: a natural molecule at the intersection of sleep and aging

“…Further, a diet supplemented with apigenin restored cardiac function and reduced the risk for isoproterenol-induced myocardial infarction in rats with streptozotocin-induced diabetes ( 98 ). In a separate mouse model of cardiomyopathy, apigenin delivered via gavage improved heart function and suppressed cardiac inflammation ( 99 ). Similarly, in a mouse model of atherosclerosis and non-alcoholic fatty liver disease, dietary apigenin reduced atherosclerosis, hepatic lipid accumulation, body weight, and plasma lipid levels ( 100 ).…”

“…Life extension also depended on the genes aak-2 , daf-16 , and skn-1 ( 94 ). Such findings are interesting given that, in a mouse model of myocardial injury, the protective effects of apigenin were dependent on the mitochondrial unfolded protein response ( 99 ).…”