microRNA-21-3p通过靶基因SORBS2调控LPS诱导的脓毒症心肌病

发布时间：2018-06-25 02:59

本文选题：脓毒症 + 心衰　；参考：《南京医科大学》2016年博士论文

【摘要】：目的：心功能不全是脓毒症及脓毒性休克时常见并发症,是危重病患者最常见的死因。近期的研究发现microRNAs (miRNAs)在脓毒症中可作为标志物发挥潜在作用,但是其在脓毒性心肌病(Sepsis-induced cardiomyopathy, SIC)的作用知之甚少。本项研究将探讨miRNAs在脓毒症心肌病中可能扮演的角色,并为临床治疗脓毒症心功能不全寻找可能的干预靶点提供理论依据。方法：C57BL/6小鼠注射脂多糖(LPS) (5mg/kg)诱导脓毒性心肌病模型,对照组给与同等剂量的生理盐水,5-7h后测心超,7-9h收取心脏标本,进行miRNAs芯片筛选与LPS诱导脓毒性心衰相关的miRNAs。通过小鼠尾静脉注射miRNA的激动剂和抑制剂,观察其在LPS刺激下对心脏功能、炎症因子、糖脂代谢、自噬等方面的影响。小鼠腹腔注射致死量脂多糖(LPS,15mg/kg),连续观察72小时记录miRNA抑制剂组小鼠的死亡情况。结果：在LPS注射后1h心功能开始下降,7-9h心功能达到最低,收取心脏组织进行miRNAs芯片筛选。我们发现8个miRNA在LPS处理后发生改变,通过进一步验证发现miR-21-3p升高倍数最高,并且在LPS注射后1h即升高,与心功能呈负相关。miR-21-3p抑制剂能改善LPS导致心功能的下降、自噬增高、线粒体超微损伤和心肌肥大,并能提高小鼠的生存率；而miR-21-3p激动剂会加重以上的表现。Sorbin和SH3结构域连接蛋白2 (SH3 domain-containing protein 2, SORBS2)与miR-21-3p在LPS组小鼠心脏组织中存在内源性调控关系,提示其可能是miR-21-3p的靶基因。与心功能正常的脓毒症患者相比,脓毒症心功能不全患者血浆中的miR-21-3p显著升高。ROC曲线结果显示线下面积为0.939,miR-21-3p是预测脓毒症心功能正常与否的一个特异性指标。结论：因此,miR-21-3p是通过抑制靶基因SORBS2,在脓毒症心肌病的发病过程中发挥着重要作用,这一结果提示miR-21-3p可能是一种治疗SIC的潜在新靶点。
[Abstract]:Objective: cardiac insufficiency is a common complication of sepsis and septic shock and the most common cause of death in critically ill patients. Recent studies have found that microRNAs (miRNAs) play a potential role as markers in sepsis, but little is known about their role in septic cardiomyopathy (sic). This study will explore the role of miRNAs in septic cardiomyopathy and provide a theoretical basis for clinical treatment of septic heart failure. Methods the septic cardiomyopathy model was induced by injection of lipopolysaccharide (5mg/kg) into mice of 10% C57BL / 6 mice. The control group was given the same dose of normal saline for 5-7 h, and the heart supernatant was measured for 7-9 h. MiRNAs microarray was used to screen miRNAs associated with LPS-induced septic heart failure. The effects of miRNA agonists and inhibitors on cardiac function, inflammatory factors, glucose and lipid metabolism and autophagy were observed by injecting miRNA into tail vein of mice. The lethal dose of lipopolysaccharide (LPSN 15 mg / kg) was injected intraperitoneally to observe the death of mice in miRNA inhibitor group for 72 hours. Results: the cardiac function began to decline at 1 h after LPS injection and the cardiac function reached the lowest at 7-9 hours. The heart tissues were selected for miRNAs microarray screening. We found that eight miRNAs changed after LPS treatment. Further verification showed that miR-21-3p had the highest increase multiple, and increased at 1 hour after LPS injection, which was negatively correlated with cardiac function. MiR-21-3p inhibitor could improve the decrease of cardiac function induced by LPS and increase autophagy. Mitochondrial ultrastructure damage, myocardial hypertrophy and survival rate of mice were increased by miR-21-3p agonists, and miR-21-3p agonists increased the expression of .Sorbin, SH3 domain-containing protein 2 (SORBS2) and miR-21-3p in LPS-treated mice. It may be the target gene of miR-21-3p. Compared with sepsis patients with normal cardiac function, miR-21-3p in plasma of septic patients with cardiac insufficiency increased significantly. The results of ROC curve showed that the area under line was 0.939 mil R-21-3p, which was a specific index to predict the normal heart function of sepsis. Conclusion: miR-21-3p may play an important role in the pathogenesis of septic cardiomyopathy by inhibiting the target gene SORBS2, which suggests that miR-21-3p may be a potential new target for the treatment of sic.
【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R459.7;R542.2

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