Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine, Beijing, 100000, China.
Int J Biol Sci. 2023 Oct 16;19(16):5233-5244. doi: 10.7150/ijbs.85204. eCollection 2023.
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). Co-administration of apigenin significantly restored heart function, reduced myocardial swelling, inhibited cardiac inflammation, increased cardiac transcription of UPR-related genes, and promoted cardiomyocyte survival in Dox-treated mice. In turn, blockade of UPR 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 knockout (KO) mice or after siRNA-mediated knockdown . We thus provide novel evidence for a promotive effect of apigenin on UPR via regulation of the Sirt1/Atf5 pathway. Our findings uncover that apigenin seems to be an effective therapeutic agent to alleviate Dox-mediated cardiotoxicity.
芹菜素是芦丁的活性成分。尽管先前的研究报告了芹菜素对阿霉素（Dox）诱导的心肌病的心脏保护作用，但潜在的机制仍不完全清楚。由于芹菜素有益地调节线粒体功能和动力学的各个方面，我们询问了芹菜素是否通过调节线粒体未折叠蛋白反应（UPR）来改善 Dox 诱导的心肌病小鼠的心脏功能。芹菜素的联合给药显著恢复了心脏功能，减少了心肌肿胀，抑制了心脏炎症，增加了 Dox 处理小鼠心脏中与 UPR 相关的基因转录，并促进了心肌细胞的存活。反过来，UPR 的阻断消除了芹菜素的线粒体和细胞保护作用，这表现在 Dox 处理的培养 HL-1 心肌细胞中 ATP 产生减少、线粒体抗氧化能力受到抑制以及细胞凋亡增加。此外，芹菜素处理可防止 Dox 诱导的 Sirt1 和 Atf5 表达下调，并且在 敲除（KO）小鼠或 siRNA 介导的 敲低 后，芹菜素的有益作用完全被消除。因此，我们为芹菜素通过调节 Sirt1/Atf5 通路促进 UPR 提供了新的证据。我们的发现表明，芹菜素似乎是一种有效的治疗剂，可以减轻 Dox 介导的心脏毒性。
