Role of selenoprotein M knockdown in the melatonin antagonism of nickel-induced apoptosis and endoplasmic reticulum stress in mouse heart

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.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/6 J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。.