Abstract
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.
摘要
心房颤动是临床上最常见的室上性心律失常, 有着较高的发病率和死亡率. 然而, 目前临床可用的相关抗心律失常药物疗效有限并具有明确的副作用. 本研究旨在探讨穿心莲内酯(Andr)对心房颤动的预防作用和潜在作用机制, 为临床治疗房颤提供新思路. 通过采用网络药理学方法, 研究Andr对房颤可能的治疗作用. 为了验证Andr在房颤中的作用, 在快速电刺激(RES)前用Andr预处理HL-1细胞1小时, 在高频心房起搏(RAP)造模前用Andr预处理1天. 分别检测细胞凋亡、 肌原纤维降解、 氧化应激和炎症等相关指标. 采用RNA测序(RNA-seq)以研究潜在作用机制. 结果表明, 在体内体外实验中, Andr治疗减轻了RAP/RES诱导的心房电生理变化、 炎症、 氧化损伤和细胞凋亡. RNA-seq表明氧化磷酸化起了重要作用. 透射电镜和ATP含量测定分别验证了线粒体的形态和功能变化. Nrf2向细胞核的易位和分子对接表明, Andr可能通过影响Keap1-Nrf2复合物发挥治疗作用. 综上所述, 本研究表明穿心莲内酯是一种潜在的能有效预防心房颤动的药物, 可通过激活Nrf2核易位和诱导HO-1的表达, 以维持线粒体的形态和功能.
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 82270317) and the Zhejiang Provincial Natural Science Foundation of China (No. LY19H020011).
The authors would like to express gratitude to EditSprings (https://www.editsprings.com) for the expert linguistic services provided.
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Conceptualization: Pengcheng YU; Data curation: Peng-cheng YU, Jiaru CAO, Huaxin SUN, and Hangying YING; Formal analysis: Pengcheng YU; Investigation: Jiaru CAO and Xinyu ZHOU; Methodology: Pengcheng YU, Jiaru CAO, Huaxin SUN, Yingchao GONG, Qingbo LV, and Hang YANG; Project administration: Ling ZHANG and Xia SHENG; Resources: Xia SHENG; Software: Huaxin SUN, Yingchao GONG, Hangying YING, Yuxing WANG, Chenyang QI, and Hang YANG; Supervision: Ling ZHANG and Xia SHENG; Visualization: Pengcheng YU, Yingchao GONG, Hangying YING, and Yuxing WANG; Writing–original draft: Pengcheng YU; Writing–review & editing: Xia SHENG and Pengcheng YU. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Pengcheng YU, Jiaru CAO, Huaxin SUN, Yingchao GONG, Hangying YING, Xinyu ZHOU, Yuxing WANG, Chenyang QI, Hang YANG, Qingbo LV, Ling ZHANG, and Xia SHENG declare that they have no conflict of interest.
All institutional and national guidelines for the care and use of laboratory animals were followed the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (NIH publication No. 85-23, revised 1996). This study was conducted with approval by the Institutional Animal Care and Use Committee of the First Affiliated Hospital of Xinjiang Medical University (Approval No. IACUC-20170420-03).
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Tables S1–S3; Fig. S1; Materials and methods
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Yu, P., Cao, J., Sun, H. et al. Andrographolide protects against atrial fibrillation by alleviating oxidative stress injury and promoting impaired mitochondrial bioenergetics. J. Zhejiang Univ. Sci. B 24, 632–649 (2023). https://doi.org/10.1631/jzus.B2300086
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DOI: https://doi.org/10.1631/jzus.B2300086