EETs抑制慢性肾衰竭中AOPPs所致血管平滑肌细胞向成骨细胞转分化的研究

Cardiovascular and cerebrovascular events are the most common complication and the leading cause death for patients with chronic renal failure. Both our previous studies and other reports demonstrated vascular calcification played an important role in this process. It was documented that advanced oxidation protein products (AOPPs) were the key for vascular calcification. We found the products of arachidonic acid metabolized by cytochrome P450 epoxygenases, epoxyeicosatrienoic acids (EETs) have the vascular protective effect in chronic renal failure. However it is still unclear that whether EETs attenuate the progress of vascular calcification and the detail mechanism has not been reported. Based on our previous and preliminary results, we raise the hypothesis that EETs inhibits the transdifferentiation of vascular smooth muscle cell into osteoblast induced by AOPPs, and attenuate vascular calcification. In this proposal, the in vivo model of vascular calcification model induced by chronic renal failure, upregulation of EETs with recombinant adenovirus and Ephx2 knock out mice, histology, flow cytometry and reverse high performance liquid chromatography are used to investigate the effect of EETs on vascular calcification. The detail mechanism of EETs-AOPPs- transdifferentiation of vascular smooth muscle cell- vascular calcification will be discussed by the in vivo model, smooth muscle cells and ion channel level. This project will provide a new therapeutic strategy for vascular calcification.

心脑血管事件是慢性肾衰竭患者最常见的并发症和首位致死因素，国内外研究和我们前期文章均证实，血管钙化在其中起重要作用，而血管平滑肌细胞向成骨细胞转分化是关键。晚期氧化蛋白产物(AOPPs)被证实与血管钙化密切相关，我们已发现花生四烯酸的细胞色素P450表氧化产物EETs对慢性肾衰竭血管病变有保护作用，然而EETs能否抑制血管钙化进程，具体机制如何，目前尚不清楚。结合前期研究和预实验结果，我们提出EETs通过抑制AOPPs诱导血管平滑肌细胞转分化，延缓血管钙化的假说，本研究拟采用小鼠慢性肾衰竭血管钙化模型，以重组腺病毒以及Ephx2基因敲除小鼠等上调EETs，在整体模型、原代血管平滑肌细胞和离子通道水平，结合组织学、流式细胞术和反向HPLC等方法研究EETs对血管钙化的作用，本研究将深入剖析EETs－AOPPs-血管平滑肌细胞表型转化--血管钙化的作用规律，为血管钙化的防治提供新的治疗策略。

心脑血管事件是慢性肾衰竭患者最常见的并发症和首位致死因素，国内外研究和我们前期文章均证实，血管钙化在其中起重要作用，而血管平滑肌细胞向成骨细胞转分化是关键。晚期氧化蛋白产物(AOPPs)被证实与血管钙化密切相关，我们已发现花生四烯酸的细胞色素P450表氧化产物EETs对慢性肾衰竭血管病变有保护作用，然而EETs能否抑制血管钙化进程，具体机制如何，目前尚不清楚。结合前期研究和预实验结果，我们提出EETs通过抑制AOPPs诱导血管平滑肌细胞转分化，延缓血管钙化的假说，本研究拟采用小鼠慢性肾衰竭血管钙化模型，以重组腺病毒以及Ephx2基因敲除小鼠等上调EETs，在整体模型、原代血管平滑肌细胞和离子通道水平，结合组织学、流式细胞术和反向HPLC等方法研究EETs对血管钙化的作用，本研究将深入剖析EETs－AOPPs-血管平滑肌细胞表型转化--血管钙化的作用规律，为血管钙化的防治提供新的治疗策略。