Melatonin attenuates ER stress and mitochondrial damage in septic cardiomyopathy: A new mechanism involving BAP31 upregulation and MAPK-ERK pathway

Jiabing Zhang; Leili Wang; Wei XieShunying HuHao ZhouPingjun ZhuHang Zhu

摘要

Septic cardiomyopathy is associated with mitochondrial damage and endoplasmic reticulum (ER) dysfunction. However, the upstream mediator of mitochondrial injury and ER stress has not been identified and thus little drug is available to treat septic cardiomyopathy. Here, we explored the role of B-cell receptor-associated protein 31 (BAP31) in septic cardiomyopathy and figure out whether melatonin could attenuate sepsis-mediated myocardial depression via modulating BAP31. Lipopolysaccharide (LPS) was used to establish the septic cardiomyopathy model. Pathway analysis was performed via western blot, quantitative polymerase chain reaction and immunofluorescence. Mitochondrial function and ER stress were detected via enzyme-linked immunosorbent assay, western blot, and immunofluorescence. After exposure to LPS, cardiac function was reduced due to excessive inflammation response and extensive cardiomyocyte death. Mechanistically, melatonin treatment could dose-dependently improve cardiomyocyte viability via preserving mitochondrial function and reducing ER stress. Further, we found that BAP31 transcription was repressed by LPS whereas melatonin could restore BAP31 expression; this effect was dependent on the MAPK-ERK pathway. Inhibition of the ERK pathway and/or knockdown of BAP31 could attenuate the beneficial effects of melatonin on mitochondrial function and ER homeostasis under LPS stress. Altogether, our results indicate that ERK-BAP31 pathway could be used as a critical mediator for mitochondrial function and ER homeostasis in sepsis-related myocardial injury. Melatonin could stabilize BAP31 via the ERK pathway and thus contribute to the preservation of cardiac function in septic cardiomyopathy.

机译：脓毒性心肌病是相关联的线粒体损伤和内质网(ER)功能障碍。线粒体损伤和ER的压力也没有被确认,因此药物可用治疗脓毒性心肌病。31 b细胞receptor-associated蛋白质的作用(BAP31)脓毒性心肌病和图褪黑激素是否能减弱sepsis-mediated通过调节BAP31心肌抑郁。脂多糖(LPS)是用于建立脓毒性心肌病模型。通过免疫印迹、执行定量吗聚合酶链反应和免疫荧光。线粒体功能和ER应激通过酶联免疫吸附试验检测,免疫印迹和免疫荧光。有限合伙人,心脏功能降低过度炎症反应和广泛的心肌细胞死亡。治疗剂量依赖性可以改善通过保护心肌细胞生存能力线粒体功能和降低ER应激。进一步,我们发现BAP31转录有限合伙人紧而褪黑激素可以恢复BAP31表达式;MAPK-ERK通路。途径和/或击倒BAP31可能减弱褪黑激素的有益影响线粒体功能和ER内稳态有限合伙人的压力。可以作为一个关键ERK-BAP31途径中介对线粒体功能和ER内稳态sepsis-related心肌损伤。褪黑素可能通过ERK BAP31稳定通路,从而有助于保护脓毒性心肌病的心脏功能。

Melatonin attenuates ER stress and mitochondrial damage in septic cardiomyopathy: A new mechanism involving BAP31 upregulation and MAPK-ERK pathway

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