1. Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
2. Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine, Beijing, 100000, China.
3. Beijing University of Chinese Medicine, Beijing, 100029, China.
4. Zhejiang Tongde Hospital, Hangzhou, 310012, China.
5. Wenzhou TCM Hospital of Zhejiang Chinese Medical University, Wenzhou, 325000, China.
6. School of Medicine, Southern University of Science and Technology (SUSTech), Shenzhen, Guangdong, China.
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 (UPRmt). Co-administration of apigenin significantly restored heart function, reduced myocardial swelling, inhibited cardiac inflammation, increased cardiac transcription of UPRmt-related genes, and promoted cardiomyocyte survival in Dox-treated mice. In turn, blockade of UPRmt 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 UPRmt via regulation of the Sirt1/Atf5 pathway. Our findings uncover that apigenin seems to be an effective therapeutic agent to alleviate Dox-mediated cardiotoxicity.
Keywords: apigenin, doxorubicin, mitochondrial unfolded protein response, Sirt1, Atf5, cardiomyopathy