Department of Critical Care Medicine, Ruijin Hospital, Lu Wan Branch, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Immun Inflamm Dis. 2023 May;11(5):e829. doi: 10.1002/iid3.829.
Cardiac dysfunction is an important component of multiple organ failure caused by sepsis, and an important cause of high mortality in patients with sepsis. Herein, we attempted to determine whether myo-inositol oxygenase (MIOX) has proinflammation enzyme in infection-induced cardiac dysfunction (IICD) and its underlying mechanism.
Patients with IICD were collected by our hospital. A mouse model of IICD was induced into male db/db mice by cecal ligation and puncture (CLP). All mice were injected with 20 μL of LV-MIOX or LV-control short hairpin RNA using a 0.5-mL insulin syringe. On the second day, all mice were induced by CLP. H9C2 cell was also induced with lipopolysaccharide and adenosine triphosphate. Quantitative analysis of messenger RNAs (mRNAs) and gene microarray hybridization was used to analyze the mRNA expression levels. Enzyme-linked immunosorbent assay, immunofluorescence, and Western blot analysis were used to analyze the protein expression levels.
The serum expressions of MIOX mRNA level in patients with IICD were upregulated compared to normal healthy volunteers. MIOX promoted inflammation levels in the in vitro model of IICD. Si-MIOX inhibited inflammation levels in the in vitro model of IICD. MIOX accelerated inflammation and cardiac dysfunction in infection-induced mice. MIOX interacted with NLR family pyrin domain containing 3 (NLRP3) protein to reduce the degradation of NLRP3. The inhibition of MIOX reversed the effects of NLRP3 in the in vitro model of cardiac dysfunction.
Taken together, these findings demonstrate that MIOX accelerates inflammation in the model of IICD, which may be, at least in part, attributable to NLRP3 activity by the suppression of NLRP3 degradation in IICD.
心脏功能障碍是脓毒症引起多器官衰竭的一个重要组成部分，也是脓毒症患者高死亡率的一个重要原因。在此，我们试图确定肌醇加氧酶（MIOX）是否在感染诱导的心脏功能障碍（IICD）及其潜在机制中具有促炎酶。
通过我院收集 IICD 患者。通过盲肠结扎和穿刺（CLP）将 IICD 小鼠模型诱导至雄性 db/db 小鼠。所有小鼠均使用 0.5mL 胰岛素注射器注射 20μL 的 LV-MIOX 或 LV-对照短发夹 RNA。第二天，所有小鼠均通过 CLP 诱导。H9C2 细胞也用脂多糖和三磷酸腺苷诱导。采用定量分析信使 RNA（mRNA）和基因微阵列杂交技术分析 mRNA 表达水平。酶联免疫吸附试验、免疫荧光和 Western blot 分析用于分析蛋白表达水平。
与正常健康志愿者相比，IICD 患者血清中 MIOX mRNA 水平上调。MIOX 促进了体外 IICD 模型中的炎症水平。Si-MIOX 抑制了体外 IICD 模型中的炎症水平。MIOX 加速了感染诱导的小鼠炎症和心脏功能障碍。MIOX 与 NLR 家族吡啶结构域包含蛋白 3（NLRP3）蛋白相互作用，从而降低 NLRP3 的降解。MIOX 的抑制作用逆转了 NLRP3 在体外心脏功能障碍模型中的作用。
综上所述，这些发现表明 MIOX 加速了 IICD 模型中的炎症，这至少部分归因于 IICD 中 NLRP3 活性通过抑制 NLRP3 降解。
