Ye Rongzong, Lin Qiuyun, Xiao Wenkai, Mao Lixia, Zhang Pengfei, Zhou Lingshan, Wu Xiaoxia, Jiang Nannan, Zhang Xihe, Zhang Yinhua, Ma Daqing, Huang Jiahao, Wang Xiaoyan, Deng Liehua
Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, China.
Doctoral Scientific Research Center, Lianjiang People's Hospital, Zhanjiang, 524400, China.
Cell Death Discov. 2023 Jan 21;9(1):19. doi: 10.1038/s41420-023-01328-x.
INTRODUCTION: Early diagnosis and potential therapeutic targets of sepsis-induced cardiomyopathy (SIC) remain challenges clinically. Circulating extracellular vesicles from immune cells carrying crucial injurious mediators, including miRNAs in sepsis. However, the impacts of neutrophil-derived extracellular vesicles and their miRNAs in the SIC development are unknown. OBJECTIVES: The present study focused on the in-depth miRNA expression profiles of neutrophil-derived extracellular vesicles and explored the potential molecular biomarkers during the process of SIC. METHODS: Neutrophil-derived extracellular vesicles were isolated from the blood samples in three sepsis patients with or without cardiomyopathy on day 1 and day 3 after ICU admission in comparison with three healthy controls. miRNAs were determined by RNA sequencing. The closely related differentially expressed miRNAs with SIC were further validated through qRT-PCR in the other cohorts of sepsis patients with (30 patients) or without cardiomyopathy (20 patients) and the association between miRNAs and the occurrence or disease severity of septic cardiomyopathy were stratified with logistic regression analysis. RESULTS: Sixty-eight miRNAs from neutrophil-derived extracellular vesicles were changed significantly between healthy controls and without septic cardiomyopathy patients (61 miRNAs upregulated and seven downregulated). Thirty-eight miRNAs were differentially expressed in the septic cardiomyopathy patients. 27 common differentially expressed miRNAs were found in both groups with similar kinetics (23 miRNAs upregulated and four downregulated). The enriched cellular signaling pathway mediated by miRNAs from sepsis to septic cardiomyopathy was the HIF-1 signaling system modulated septic inflammation. Using multivariate logistic regression analysis, miR-150-5p coupled with NT-pro BNP, LVEF, and SOFA score (AUC = 0.941) were found to be the independent predictors of septic cardiomyopathy. CONCLUSION: miRNAs derived from neutrophil-derived extracellular vesicles play an important role in septic disease severity development towards cardiomyopathy. miR-150-5p may be a predictor of sepsis severity development but warrants further study.
引言：脓毒症诱导的心肌病（SIC）的早期诊断和潜在治疗靶点在临床上仍然是挑战。来自免疫细胞的循环细胞外囊泡携带关键的损伤介质，包括脓毒症中的微小RNA（miRNA）。然而，中性粒细胞衍生的细胞外囊泡及其miRNA在SIC发生发展中的作用尚不清楚。 目的：本研究聚焦于中性粒细胞衍生的细胞外囊泡的深度miRNA表达谱，并探索SIC过程中的潜在分子生物标志物。 方法：从3例脓毒症患者（有或无心肌病）入住重症监护病房（ICU）第1天和第3天的血样中分离出中性粒细胞衍生的细胞外囊泡，并与3例健康对照进行比较。通过RNA测序确定miRNA。通过qRT-PCR在另外一组有（30例患者）或无心肌病（20例患者）的脓毒症患者中进一步验证与SIC密切相关的差异表达miRNA，并通过逻辑回归分析对miRNA与脓毒症性心肌病的发生或疾病严重程度之间的关联进行分层。 结果：健康对照与无脓毒症性心肌病患者之间，中性粒细胞衍生的细胞外囊泡中有68种miRNA发生了显著变化（61种miRNA上调，7种下调）。38种miRNA在脓毒症性心肌病患者中差异表达。两组中发现27种共同的差异表达miRNA，其动力学相似（23种miRNA上调，4种下调）。从脓毒症到脓毒症性心肌病，由miRNA介导的富集细胞信号通路是HIF-1信号系统调节的脓毒症炎症。使用多因素逻辑回归分析，发现miR-150-5p与NT-pro BNP、左室射血分数（LVEF）和序贯器官衰竭评估（SOFA）评分（AUC = 0.941）是脓毒症性心肌病的独立预测指标。 结论：中性粒细胞衍生的细胞外囊泡来源的miRNA在脓毒症向心肌病发展的疾病严重程度中起重要作用。miR-150-5p可能是脓毒症严重程度发展的预测指标，但有待进一步研究。
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