LMO4上调诱导内皮细胞炎性激活促进动脉粥样硬化的机制研究

遗传因素在冠心病的发生发展中发挥着重要作用，然而相关基因及其机制仍有待充分挖掘。本课题组前期通过对520例冠心病患者进行DNA甲基化分析，发现多个位点甲基化率与疾病严重程度高度相关，提示作为预后生物标志物的潜能。其中，LMO4基因启动子区cg26801613位点甲基化率与死亡风险呈高度负相关。初步研究发现，该位点去甲基化调控基因表达上调；内皮细胞过表达LMO4激活JAK/STAT3通路，上调黏附因子并促进单核细胞黏附，呈炎性激活表型。据此推测LMO4上调诱导内皮细胞炎性激活促进斑块形成，干预LMO4可减缓疾病进展。本项目将：①动物模型病理切片评价LMO4与斑块形成的相关性；②在ApoE敲除小鼠中用AAV载体上下调LMO4评价斑块形成是否受影响；③互作组学研究LMO4通过JAK/STAT3通路调控内皮细胞炎性激活的机制。本项目将为临床上治疗动脉粥样硬化潜在靶标提供理论和实验基础。

Genetic factors play an important role in the occurrence and development of coronary heart disease (CHD), while the associated genes and their mechanisms remain to be fully explored. Through DNA methylation analysis of 520 CHD patients, our research group found multiple sites which methylation rate were highly correlated with the severity of disease, suggesting its potential as a prognostic biomarker. The methylation rate of cg26801613 in the LMO4 promoter was highly negatively correlated with the risk of death. Preliminary studies showed that its de-methylation up-regulates LMO4 and endothelial cells overexpressed LMO4 showed an inflammatory activation phenotype, promoting monocyte adhesion through activation of JAK/STAT3 pathway and up-regulation of adhesion factors. Therefore, we speculate that LMO4 up-regulation induces endothelial proinflammatory activation and contributed to plaque formation, and the intervention of LMO4 can slow disease progression. This project will : 1) evaluate the correlation between LMO4 and plaque formation by pathological sections of animal models; 2) observe whether plaque formation was affected by up- or down-regulating LMO4 via AAV vectors in ApoE knockout mice; 3) study how LMO4 regulates endothelial proinflammatory activation by JAK/STAT3 pathway viainteraction omics. This project will provide theoretical and experimental basis for new potential clinical targets of atherosclerosis.