脂肪细胞外泌体lncRNA NBR2通过hnRNPK/SETDB1复合体调控IκBα/NF-κB通路介导糖尿病心肌纤维化的机制研究

糖尿病心肌病（DCM）是糖尿病患者主要死因，其重要特征为心肌纤维化。申请人前期报道，阻断NF-κB通路可抑制DCM心肌纤维化，但上游机制未明。我们运用基因芯片筛选发现高糖刺激的脂肪细胞外泌体lncRNA NBR2（AdEXO-NBR2）水平显著上调，并进入成人心肌成纤维细胞 （aHCFs）激活NF-κB通路，促进心肌纤维化。进一步预实验：lncRNA NBR2在aHCFs中将hnRNPK和SETDB1锚定至IκBα启动子，通过SETDB1下调IκBα表达。因此本项目提出科学假说：AdEXO-NBR2通过hnRNPK/SETDB1复合体抑制aHCFs中IκBα表达，从而激活NF-κB通路，促进糖尿病心肌纤维化。本研究从高糖环境中脂肪及心脏“交叉对话”新视角，聚焦lncRNA表观调控作用，揭示AdEXO-NBR2介导糖尿病心肌纤维化的分子机制，为DCM防治提供新的理论依据和治疗靶点。

Diabetic cardiomyopathy (DCM) is one of the leading causes of death in diabetic patients, characterized by myocardial fibrosis leading to diastolic dysfunction. Our previous study revealed that diabetic myocardial fibrosis was alleviated by blockage of the NF-κB pathway. However, the underlying upstream mechanism remains to be understood. Using gene chip technologies for screening, we identified levels of adipocyte-derived exosomal lncRNA NBR2 (AdEXO-NBR2) induced by hyperglycemia were significantly elevated, which in turn promoted myocardial fibrosis by entering adult human cardiac fibroblasts (aHCFs) and activating the NF-κB pathway. Further pilot study showed that lncRNA NBR2 bound the IκBα promoter and recruited hnRNPK and SETDB1 to inhibit the transcriptional activity of IκBα via increasing the methylation of core histone. In light of these, we hereby proposed a mechanistic hypothesis that AdEXO-NBR2 cooperated with hnRNPK/SETDB1 complex would promote diabetic myocardial fibrosis by inhibition of IκBα expression and activation of the NF-κB pathway in aHCFs. From a new perspective of "CROSS TALK" between fat and heart in high glucose milieu, this project aims to focus on the epigenetic regulation of lncRNA, elucidate the molecular mechanisms of AdEXO-NBR2 mediated DCM myocardial fibrosis, and provide a new therapeutic target and rationale for DCM prevention and treatment.