Upregulation of Heme Oxygenase-1 by Hemin Alleviates Sepsis-Induced Muscle Wasting in Mice
Upregulation of Heme Oxygenase-1 by Hemin Alleviates Sepsis-Induced Muscle Wasting in Mice
复制标题
血红素上调血红素加氧酶 1 可减轻脓毒症引起的小鼠肌肉萎缩
DOI：
10.1155/2018/8927104
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Deng, Xiaoming
中科院分区：
文献类型：
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作者：
Yu, Xiongwei;Han, Wenjun;Deng, Xiaoming
血红素是血红素氧合酶-1（HO-1）的诱导剂，可增强HO-1的活化。HO-1具有抗炎、抗氧化、抗凋亡等多种生物活性。本研究的目的是研究氯化血红素对脓毒症引起的骨骼肌萎缩的影响，并探讨氯化血红素发挥其作用的机制。进行盲肠结扎和穿孔（CLP）以创建脓毒症小鼠模型。将小鼠随机分为4组：对照组、CLP组、CLP+组和CLP-hemin-ZnPP（HO-1抑制剂）组。测量小鼠足跖重量，并进行组织病理学检查。酶联免疫吸附试验（ELISA）测定细胞因子。采用实时定量逆转录聚合酶链反应（qRT-PCR）和Western印迹法检测HO-1和atrogin-1的表达水平。此外，我们研究了HO-1的抗氧化作用，通过检测丙二醛（MDA）水平和超氧化物歧化酶（SOD）活性。CLP导致了剧烈的骨骼肌无力和萎缩，但用氯化血红素预处理可保护小鼠免受CLP介导的肌肉萎缩。血红素还诱导高HO-1表达，这导致抑制促炎细胞因子和活性氧（ROS）的产生。MuRF 1和atrogin-1的表达，泛素-蛋白酶体系统（UPS-）介导的蛋白水解的两个泛素连接酶，也被HO-1水平的增加抑制。血红素介导的HO-1表达增加对脓毒症诱导的骨骼肌萎缩发挥保护作用，至少部分通过抑制促炎细胞因子的表达，UPS介导的蛋白水解和ROS活化。因此，氯化高铁血红素可能成为脓毒症诱导的骨骼肌萎缩的一个新的治疗靶点。
Hemin, an inducer of heme oxygenase-1 (HO-1), can enhance the activation of HO-1. HO-1 exhibits a variety of activities, such as anti-inflammatory, antioxidative, and antiapoptotic functions. The objective of this study was to investigate the effects of hemin on sepsis-induced skeletal muscle wasting and to explore the mechanisms by which hemin exerts its effects. Cecal ligation and perforation (CLP) was performed to create a sepsis mouse model. Mice were randomly divided into four groups: control, CLP, CLP plus group, and CLP-hemin-ZnPP (a HO-1 inhibitor). The weight of the solei from the mice was measured, and histopathology was examined. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to assess the expression levels of HO-1 and atrogin-1. Furthermore, we investigated the antioxidative effects of HO-1 by detecting malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. CLP led to dramatic skeletal muscle weakness and atrophy, but pretreatment with hemin protected mice against CLP-mediated muscle atrophy. Hemin also induced high HO-1 expression, which resulted in suppressed proinflammatory cytokine and reactive oxygen species (ROS) production. The expression of MuRF1 and atrogin-1, two ubiquitin ligases of the ubiquitin-proteasome system- (UPS-) mediated proteolysis, was also inhibited by increased HO-1 levels. Hemin-mediated increases in HO-1 expression exert protective effects on sepsis-induced skeletal muscle atrophy at least partly by inhibiting the expression of proinflammatory cytokines, UPS-mediated proteolysis, and ROS activation. Therefore, hemin might be a new treatment target against sepsis-induced skeletal muscle atrophy.