NLRP3炎症小体/caspase-1调控通路在肥胖心肌损伤中的作用及其机制研究

NLRP3 inflammasome was one of the members of the NLR family of pattern recognition receptors, involved in intracellular inflammatory reaction. The activation of NLRP3 inflammasome was an important link in the development of obesity induced lipid accumulation. Accumulating adipose tissue released inflammatory mediators which entered the circulatory system and caused cardiac remodeling. We used strain technique to find that the regional myocardial function was decreased in patients with obesity. However, the specific mechanism was not clear. Therefore, it was speculated that the obese patient was damage through the NLRP3/caspase-1 pathway mediated pyroptosis for destruction of the homeostasis of the cell micro-environment, caused cardiac remodeling and myocardial systolic function damage. Obese mice were used as the research objects. Application of ultrasound biomicroscopy dynamicly in vivo observed NLRP3-miRNA interventing mice and myocardial systolic function of normal mice in control group, to analyze correlation of NLRP3/caspase-1 pathway and obesity myocardial damage. Though high fat myocardial cells cultured in vitro to investigated the effect of NLRP3/caspase-1 pathway caused myocardial pyroptosis, so as to clarify the regulation mechanism of the NLRP3/caspase-1pathway caused cardiac muscle cell pyroptosis and Key factors change, it might provided a new theoretical basis for the early diagnosis of myocardial injury, the degree of evaluation and a new target for intervention and therapy.

NLRP3 炎症小体是胞内模式识别受体NLR 家族成员之一，参与炎症反应。NLRP3炎症小体的激活是脂质蓄积诱导肥胖发展的重要环节，堆积的脂肪组织释放炎症介质进入循环系统可以引起心肌重构。我们前期应用应变技术观察到肥胖患者存在局部心肌收缩功能降低，但具体机制尚不明确。推测肥胖患者通过NLRP3/caspase-1通路介导细胞焦亡对细胞微环境稳态进行破坏，引起心肌重构，损伤了心肌收缩功能。本课题以肥胖小鼠模型为研究对象，应用超声生物显微镜活体观察NLRP3-miRNA干预肥胖小鼠及对照小鼠的心肌收缩功能，分析NLRP3/caspase-1通路与肥胖心肌损伤的相关性；通过体外高脂心肌细胞培养来探讨NLRP3/caspase-1通路对心肌细胞焦亡的影响，从而阐明NLRP3/caspase-1通路对心肌细胞焦亡的调控机制及关键因子变化，为肥胖心肌损伤诊断提供新的理论依据和干预治疗靶点。

NLRP3炎症小体是胞内模式识别受体NLR家族成员之一，参与炎症反应。NLRP3炎症小体的激活是脂质蓄积诱导肥胖发展的重要环节，堆积的脂肪组织释放炎症介质进入循环系统可以引起心肌重构。我们前期应用应变技术观察到肥胖患者存在局部心肌收缩功能降低，但具体机制尚不明确。本项目研究发现肥胖小鼠通过NLRP3/caspase-1通路介导细胞焦亡对细胞微环境稳态进行破坏，引起心肌重构，损伤了心肌收缩功能。本课题以肥胖小鼠模型为研究对象，显微镜活体观察NLRP3-miRNA干预肥胖小鼠及对照小鼠的心肌收缩功能，结果表明肥胖小鼠左室心肌功能改变与NLRP3/caspase-1通路具有明显相关性；从而阐明肥胖小鼠通过NLRP3/caspase-1通路对心肌细胞焦亡的调控机制及关键因子变化，为肥胖心肌损伤诊断提供新的理论依据和干预治疗靶点。