Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway.

苦参碱通过维持 AMPK α / UCP2 通路减轻多柔比星诱导的心脏毒性中的氧化应激和心肌细胞凋亡。

• 影响指数: 14.903
• 发表时间: Jul 2019
• 来源期刊: Acta Pharm Sin B
• DOI: 10.1016/j.apsb.2019.03.003
• PMID: 31384530
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 医学
• 作者列表: Hu C,Zhang X,Wei W,Zhang N,Wu H,Ma Z,Li L,Deng W,Tang Q

关键词: 4-HNE, 4-hydroxynonenal; ACC, acetyl-CoA carboxylase; AMPKα; AMPKα, 5′-AMP-activated protein kinase α; ANOVA, analysis of variance; Apoptosis; BAX, BCL-2-associated X protein; BCA, bicinchoninic acid; BCL-2, B-cell lymphoma 2; C-caspase 3, cleaved-caspase3; CCK-8, cell counting kit 8; CK-MB, creatine kinase isoenzymes; DCFH-DA, 2′,7′-dichlorodihydrofluorescein diacetate; DHE, dihydroethidium; DMEM, Dulbecco׳s modified Eagle׳s medium; DOX, doxorubicin; FBS, fetal bovine serum; FS, fractional shortening; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HW, heart weight; LDH, lactate dehydrogenase; MDA, malondialdehyde; Matrine; Oxidative stress; PPARs, peroxisomal proliferators-activated receptors; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; T-caspase3, total-caspase3; TL, tibia length; TUNEL, TdT-mediated dUTP nick end-labelling; Top2, topoisomerase-II; UCP2; UCP2, uncoupling protein 2; cTnT, cardiac isoform of Tropnin T

Abstract

Oxidative stress and cardiomyocyte apoptosis are involved in the pathogenesis of doxorubicin (DOX)-induced cardiotoxicity. Matrine is well-known for its powerful anti-oxidant and anti-apoptotic capacities. Our present study aimed to investigate the effect of matrine on DOX-induced cardiotoxicity and try to unearth the underlying mechanisms. Mice were exposed with DOX to generate DOX-induced cardiotoxicity or normal saline as control. H9C2 cells were used to verify the effect of matrine in vitro. DOX injection triggered increased generation of reactive oxygen species (ROS) and excessive cardiomyocyte apoptosis, which were significantly mitigated by matrine. Mechanistically, we found that matrine ameliorated DOX-induced uncoupling protein 2 (UCP2) downregulation, and UCP2 inhibition by genipin could blunt the protective effect of matrine on DOX-induced oxidative stress and cardiomyocyte apoptosis. Besides, 5\'-AMP-activated protein kinase α2 (Ampkα2) deficiency inhibited matrine-mediated UCP2 preservation and abolished the beneficial effect of matrine in mice. Besides, we observed that matrine incubation alleviated DOX-induced H9C2 cells apoptosis and oxidative stress level via activating AMPKα/UCP2, which were blunted by either AMPKα or UCP2 inhibition with genetic or pharmacological methods. Matrine attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway, and it might be a promising therapeutic agent for the treatment of DOX-induced cardiotoxicity.

摘要

氧化应激和心肌细胞凋亡参与阿霉素（DOX）诱导的心脏毒性的发病机制。苦参碱以其强大的抗氧化和抗凋亡能力而闻名。本研究旨在研究苦参碱对DOX诱导的心脏毒性的影响，并试图揭示其潜在机制。小鼠暴露于DOX以产生DOX诱导的心脏毒性或生理盐水作为对照。用H9C2细胞体外验证苦参碱的感化。DOX注射引发活性氧（ROS）产生增加和心肌细胞凋亡过度，苦参碱可显着减轻。机械上,我们发现苦参碱改善了DOX诱导的解偶联蛋白2（UCP2）的下调，京尼平抑制UCP2可以减弱苦参碱对DOX诱导的氧化应激和心肌细胞凋亡的保护作用。此外,5'-AMP激活的蛋白激酶α2（Ampkα2）缺乏症抑制了苦参碱介导的UCP2保存，并消除了苦参碱对小鼠的有益作用。此外,我们观察到苦参碱孵育通过激活AMPKα/UCP2减轻DOX诱导的H9C2细胞凋亡和氧化应激水平，通过遗传或药理学方法抑制AMPKα或UCP2减弱。苦参碱通过维持AMPKα/UCP2通路减轻DOX诱导的心肌氧化应激和心肌细胞凋亡,它可能是治疗DOX引起的心脏毒性的有前途的治疗剂。