IL-6基因敲除抑制压力后负荷增加诱导的心肌肥大和心功能不全

发布时间：2018-04-05 00:28

本文选题：心肌肥大　切入点：白细胞介素-6　出处：《华中科技大学》2016年博士论文

【摘要】：目的：阐明基因敲除白细胞介素-6 (interleukin-6, IL-6)抑制压力后负荷增加诱导的病理性心肌肥大,保护心脏功能,减缓向心力衰竭的病程转化；探索IL-6诱导病理性心肌肥大的相关分子机制。方法与结果：通过对成年C57BL/6J (wild type, WT)小鼠及与其年龄和体重相吻合的IL-6基因敲除(IL-6 knock out, IL-6 KO)小鼠实施经胸主动脉缩窄术(transverse aortic constriction, TAC),建立压力后负荷增加诱导的心肌肥大模型,超声心动图及血流动力学检测显示基因敲除IL-6显著抑制压力后负荷增加诱导的心肌肥大,保护心脏收缩和舒张功能,减轻心肌纤维化及心肌细胞凋亡。同时,TAC诱导的细胞转导和转录激活因3(signal transducer and activator of transcription 3, STAT3)及钙离子／钙调素依赖性蛋白激酶II (Ca2+/calmodulin-dependent protein, CaMKII)活性在IL-6 KO小鼠中被显著抑制。体外实验进一步证实基因敲除IL-6显著抑制不同促心肌肥大药物诱导的成年小鼠原代心肌细胞及H9c2细胞肥大。另一方面,通过基因过表达及药物抑制的方法阐明CaMKII调控IL-6诱导的STAT3活性。结论：基因敲除IL-6显著抑制压力后负荷增加引起的心肌肥大,减缓心室重构和心功能不全,表明IL-6在压力后负荷诱导的病理性心肌肥大中的重要作用。值得注意的是阐明CaMKII是IL-6诱导的心肌肥大的重要调控因子,调控IL-6诱导的STAT3活性。这些发现可能为减少系统性高血压病人的心肌肥大以及心功能不全提供潜在的治疗方案。
[Abstract]:Aim: to elucidate the inhibitory effect of interleukin-6 (IL-6) knockout on the pathological myocardial hypertrophy induced by pressure afterload, protect cardiac function and slow down the transition to heart failure, and explore the molecular mechanism of pathological myocardial hypertrophy induced by IL-6.Methods and results: transverse aortic constriction was performed on adult C57BL/6J wild type (WTT) mice and IL-6 gene knockout (IL-6 KOO) mice, which were matched with their age and body weight. The model of myocardial hypertrophy was established by transverse aortic constriction.Echocardiography and hemodynamic examination showed that knockout IL-6 significantly inhibited myocardial hypertrophy induced by increased pressure afterload, protected cardiac contractile and diastolic function, and alleviated myocardial fibrosis and cardiomyocyte apoptosis.At the same time, the activation of cell transduction and transcription induced by TAC was significantly inhibited by 3(signal transducer and activator of transcription 3 (STAT3) and Ca 2 + / calmodulin-dependent protein (CaMK II) activity in IL-6 KO mice.In vitro experiments further confirmed that knockout IL-6 significantly inhibited primary cardiomyocyte and H9c2 cell hypertrophy induced by different hypertrophic drugs in adult mice.On the other hand, CaMKII regulates the STAT3 activity induced by IL-6 by gene overexpression and drug inhibition.Conclusion: knockout IL-6 can significantly inhibit myocardial hypertrophy induced by increased pressure after loading, and slow down ventricular remodeling and cardiac insufficiency, suggesting that IL-6 plays an important role in pressure-induced pathological myocardial hypertrophy.It is worth noting that CaMKII is an important regulatory factor of myocardial hypertrophy induced by IL-6 and regulates the STAT3 activity induced by IL-6.These findings may provide a potential therapy for reducing myocardial hypertrophy and cardiac insufficiency in patients with systemic hypertension.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R542.2

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