Abstract
The aim of this study was to investigate the role of selenoprotein M (SelM) in endoplasmic reticulum stress and apoptosis in nickel-exposed mouse hearts and to explore the detoxifying effects of melatonin. At 21 d after intraperitoneal injection of nickel chloride (NiCl2) and/or melatonin into male wild-type (WT) and SelM knockout (KO) C57BL/6J mice, NiCl2 was found to induce changes in the microstructure and ultrastructure of the hearts of both WT and SelM KO mice, which were caused by oxidative stress, endoplasmic reticulum stress, and apoptosis, as evidenced by decreases in malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) activity. Changes in the messenger RNA (mRNA) and protein expression of genes related to endoplasmic reticulum stress (activating transcription factor 4 (ATF4), inositol-requiring protein 1 (IRE1), c-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP)) and apoptosis (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Caspase-9, and Caspase-12) were also observed. Notably, the observed damage was worse in SelM KO mice. Furthermore, melatonin alleviated the heart injury caused by NiCl2 in WT mice but could not exert a good protective effect in the heart of SelM KO mice. Overall, the findings suggested that the antioxidant capacity of SelM, as well as its modulation of endoplasmic reticulum stress and apoptosis, plays important roles in nickel-induced heart injury.
摘要
本研究旨在研究硒蛋白 M (SelM) 在由镍诱导的小鼠心脏内质网应激和细胞凋亡中的作用, 并探索褪黑素的解毒作用. 在对雄性野生型 (WT) 和 SelM 敲除型 (KO) C57BL/6J 小鼠腹腔注射氯化镍 (NiCl2)和/或褪黑素 21 天后, 我们发现 NiCl2能诱发WT和 SelM KO 小鼠心脏的微观结构和超微结构的变化, 并通过丙二醛 (MDA) 含量和总抗氧化能力 (T-AOC) 下降证明这些变化是由氧化应激、 内质网应激和细胞凋亡引起的. 同时, 我们观察到与内质网应激(激活转录因子 4 (ATF4)、 肌醇需要酶 1 (IRE1)、 c-Jun N-端激酶 (JNK) 和 C/EBP 同源蛋白 (CHOP)) 和细胞凋亡( B 细胞淋巴瘤 2 型蛋白 (Bcl-2)、 Bcl-2 相关蛋白 X (Bax)、 半胱氨酸-天冬氨酸蛋白酶 3 (Caspase-3)、 Caspase-9 和 Caspase-12) 相关基因的信使 RNA (mRNA) 和蛋白表达的变化. 值得注意的是, 这种损伤在 SelM KO 小鼠中更严重. 此外, 褪黑素减轻了 WT 小鼠由 NiCl2 引起的心脏损伤, 但对 SelM KO 小鼠的心脏却不能产生良好的保护作用. 综上所述, 本研究结果表明 SelM 的抗氧化能力以及它对内质网应激和细胞凋亡的调节在镍引起的心脏损伤中起着重要作用.
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The work was supported by the Heilongjiang Provincial Natural Science Foundation for Outstanding Youth (No. YQ2021C021), China.
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Xintong ZHANG: writing - original draft; Xiaoxue GAI: data curation; Lihua XU: software; Wenxue MA: validation; Qiaohan LIU: visualization; Bendong SHI: methodology; Cheng FANG and Jingzeng CAI: writing - review & editing; Ziwei ZHANG: funding acquisition. 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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Xintong ZHANG, Xiaoxue GAI, Lihua XU, Wenxue MA, Qiaohan LIU, Bendong SHI, Cheng FANG, Jingzeng CAI, and Ziwei ZHANG declare that they have no conflict of interests.
All procedures were carried out following the directive of the Council of the European Communities (No. 86/609/EEC) and approved by the Committee on Animal Management and Use of Northeast Agricultural University (No. SRM-11), China.
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Zhang, X., Gai, X., Xu, L. et al. Role of selenoprotein M knockdown in the melatonin antagonism of nickel-induced apoptosis and endoplasmic reticulum stress in mouse heart. J. Zhejiang Univ. Sci. B 24, 406–417 (2023). https://doi.org/10.1631/jzus.B2200694
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DOI: https://doi.org/10.1631/jzus.B2200694