miR-155通过SHIP-1/p53MAPK/STAT3介导Th17细胞分化在盐敏感性高血压左室肥厚中的作用机制研究

Pathological differentiation of Th17 cell plays an important role in the pathogenesis of hypertension, and Th17 cells and IL-17A may also participate in hypertrophying and remodeling left ventricular in patients with salt-sensitive hypertension. Our previous studies showed that he proportion of Th17 cells was increased, and the expression of miR-155 was up-regulated, meanwhile the expression of SHIP1 was down-regulated and the phosphorylation of p53 MAPK and STAT3 was increased in CD4+T cell in peripheral blood of patients with salt-sensitive hypertension. SHIP1 is a negative regulator of p53 MAPK and SHIP1 may be a target gene of miR-155. Therefore, we hypothesize that the expression of miR-155 in patients with salt-sensitive hypertension is elevated, inhibiting SHIP1 precisely , activating p53 MAPK/STAT3 pathway, promoting Th17 cell differentiation and release of IL-17A, to hypertrophy left ventricular. In this study, we will isolate the CD4+ T cells cultured peripheral blood in high-salt environments, construct a rat model with salt-induced hypertension, as well as use gene introduction, gene interference in molecular, cell and animal experiments to verify this hypothesis and explore the immune mechanism of salt-induced hypertensive left ventricular hypertrophy. This study will provide a new target for the prevention of hypertensive damage on organ and reversal of left ventricular hypertrophy especially.

病理性Th17细胞分化在高血压发病中起重要作用，而Th17细胞和IL-17A可能也参与盐敏感高血压左室肥厚、重构。我们前期研究表明，盐敏感高血压患者外周血CD4+T细胞miR-155表达上调，Th17细胞比例增高；同时，细胞SHIP1表达下调，p53MAPK和STAT3磷酸化水平增高。而SHIP1是p53MAPK负调控子，SHIP1可能是miR-155靶基因。因此，我们推测：盐敏感高血压miR-155表达升高，靶向抑制SHIP1，激活p53MAPK/STAT3，促进Th17细胞分化和释放IL-17A，引起左室肥厚。为验证这一假说，本研究拟分离培养外周血CD4+T细胞并在高盐环境中培养，构建盐诱导高血压大鼠模型，并分别在分子、细胞及动物实验采用基因导入、基因干扰、分子抑制剂等方法，探索盐诱导高血压左室肥厚的免疫机制，为高血压靶器官损害尤其是左心室肥厚的逆转提供新的干预靶点。

本项目用3%氯化钠饲养大鼠构建盐诱导性高血压模型，探讨过表达/低表达SHIP-1对心肌组织SHIP-1、STATA3、IL-6变化及心室肥厚和纤维化的影响。结果显示：盐诱导高血压大鼠SHIP-1表达下调，而STATA3和IL-6表达上调，心脏/体重比值增大、心肌间质胶原纤维沉积明显增加，而过表达SHIP-1可使心肌组织STATA3、磷酸化的STATA3和IL-6表达下调，心肌间质纤维沉积减少，低表达SHIP-1则呈现相反趋势。证明SHIP-1有可能通过负性调控STATA3/IL-6信号逆转左心室肥厚，经双荧光素酶报告基因检测证实SHIP-1是miR-155的靶基因，提示miR-155介导SHIP-1/STATA3/IL-6轴参与左室肥厚。.通过粪便 16S rRNA 测序发现：盐诱导性高血压大鼠肠道菌群生态失调，与正常对照组大鼠相比，盐诱导性高血压大鼠(SSH)的粪便微生物多样性降低，韦荣球菌科、梭杆菌科、拟普雷沃氏菌属和普雷沃氏菌科丰度下降，而疣微菌科丰度增加；通过ROC曲线分析发现瘤胃菌属-1(Ruminococcus_1)的AUC面积>0.95，可作为盐诱导性高血压的肠道菌群生物标记物。. 此外，我们利用转录组学和代谢组学检测盐敏感高血压和耐盐高血压患者外周血单核细胞的基因表达和代谢产物差异，发现了6个关键的差异基因（SIK1、PLA2R1、PDFGRA、CTRP4、FGFR2和ATP1A4），而代谢产物差异主要富集于胆汁酸代谢、脂肪酸代谢和类固醇类代谢。这为进一步深入研究盐敏感高血压的发病机制提供了良好的基础。. 综上所述，本项目初步阐明了miR-155可能通过调控SHIP-1/STATA3/IL-6轴，参与盐诱导高血压左心室肥厚的发生，并发现瘤胃菌属-1有可能作为盐诱导性高血压的肠道菌群生物标记物。同时，发现了盐敏感高血压与耐盐高血压患者关键的差异基因和主要代谢产物，为多维度探索盐敏感高血压发病机制提供了基础。

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