Notch-miRNA221通路在PTH诱导CKD心脏瓣膜钙化形成中的作用研究

Cardiac valve calcification (CVC) is one of the severe cardiovascular complications in chronic kidney disease (CKD). It is the important risk factor for cardiovascular mortality among patients with CKD. However, the exact mechanism of the CVC has not been completely elucidated. Recent studies showed that conversion of endothelial phenotypic transition could be triggered into osteoblasts involving in the CVC. Our preliminary experiment indicated that PTH could induce the phenotypic change of the aortic endothelial cells in vivo and in vitro. And the undergoing endothelial phenotypic transition cells also showed expression of the STRO-1 comparing to controls. Notch-miRNA221 might involve in the progress. CKD rats could present with renal endothelial phenotypic transition in very early stage. On the basis of previous research, the cardiac valve endothelial cells culture and rat models of CKD will be used to explore the effect and mechanism of PTH on cardiac valve endothelial phenotypic transition by the ways of micro CT, pathological changes and molecular techniques. Furthermore, whether PTH-induces cardiac valve endothelial phenotypic transition will transform into osteoblasts could contribute to the CVC in CKD will be investigated. And the Notch-miRNA221 pathway will be explored. This study will provide novel insight into the development of CKD and finally contribute to the establishment of new strategy of CVC prevention in CKD.

心脏瓣膜钙化是CKD严重的心血管并发症（CVD），是导致CKD 患者心血管死亡率增加的重要危险因素。CKD心瓣膜钙化的具体机制仍不清楚。最近研究表明，心瓣膜内皮-成骨样细胞转分化可能参与心瓣膜钙化的形成，而内皮Notch-miRNA221通路激活可能与此有关。我们在体外实验中发现，PTH可以诱导内皮细胞转化成骨样细胞促进血管钙化。本研究拟在前期工作基础上，通过体外心脏瓣膜内皮细胞培养以及多种CKD大鼠及转基因小鼠模型，利用CT、病理、分子生物学等多种手段，着重探讨PTH诱导的内皮-成骨转分化在CKD心脏瓣膜钙化中的作用，以及Notch-miRNA221信号通路激活在其中的作用，以阐明CKD患者心脏瓣膜钙化形成机制，为临床早期防治CKD患者CVD提供新思路。

心脏瓣膜钙化是CKD严重的心血管并发症（CVD），是导致CKD患者心血管死亡率增加的重要危险因素。本项目旨在探讨：PTH诱导的内皮-成骨转分化在CKD心脏瓣膜钙化中的作用，以及Notch1信号通路激活在其中的作用，以阐明CKD患者心脏瓣膜钙化形成机制。主要研究结果如下：1）构建CKD大鼠心脏多瓣膜钙化模型；2）PTH诱导的内皮间充质转分化（EndMT）参与CKD心脏瓣膜组织钙化的发生发展。CINA下调PTH可以抑制心脏瓣膜发生内皮间充质转分化；3）PTH通过结合PTHR1下调miR-29a-5p的表达水平，从而上调GASP蛋白的表达水平 ，进一步激活γ-分泌酶以及其底物NICD，NICD上调核内Hes1的表达水平，激活Notch1信号通路，从而诱导了内皮间充质转分化。4）高磷干预可以诱导 VICs 发生活化；aVICs 通过释放 CXCL8 介导 VECs 发生 EndMT，其可能通过 miR-214-3p/ PTEN/ Akt 通路调节；当抑制 VECs End-MT 时，可以缓解瓣膜钙化。项目执行期间已发表SCI论著9篇，累积影响因子47.803分，3分以上8篇。