EETs 激活PPAR-γ抑制慢性肾衰高磷所致血管平滑肌细胞表型转化研究

Cardiovascular events are the leading cause of death for patients with chronic renal failure (CRF). Recent studies demonstrated that vascular calcification (VC) played an important role in this process. And the transdifferentiation of vascular smooth muscle cells (VSMCs) is the key mechanism of VC. Our previous studies found that epoxyeicosatrienoic acids (EETs) have the cardiovascular protective effect in CRF. However, whether EETs could attenuate VC and what is the detail mechanism has not been known. Furthermore, Peroxisome proliferator-activated receptor γ(PPAR-γ) is found to have association with VC. Based on our previous and preliminary results, we raise the hypothesis that EETs could inhibit the transdifferentiation of VSMCs through activating PPAR-γ, and prevent VC. In this study, We will exolore the effect of EETs on VC in CRF patients ,animal model, and cell levels by using in vivo model of VC induced by CRF, and upregulation of EETs by Ephx2 knock out and sEH inhibition. The detail mechanism of EETs- PPAR-γ- transdifferentiation of VSMCs- VC will be deeply investigated. This project will provide a new therapeutic intervention for VC.

心血管事件是慢性肾衰竭 (CRF)患者首位致死因素。新近研究表明血管钙化(VC)在其中起着重要作用。而血管平滑肌细胞(VSMCs)表型转化是VC的重要机制。我们前期研究发现环氧二十碳三烯酸（EETs）具有心血管保护作用，然而EETs能否抑制VC，具体机制如何，目前尚不清楚。此外，过氧化物酶增殖物激活受体γ(PPAR-γ)也被证实与VC密切相关。结合前期研究和预实验结果，我们提出EETs通过激活PPAR-γ抑制VSMCs表型转化，进而抑制VC的假说。本研究拟采用小鼠CRF血管钙化模型，以Ephx2基因敲除及EETs代谢关键酶sEH抑制剂上调EETs，在人群、动物、细胞水平上探讨EETs对VC的作用。本研究旨在深入剖析EETs－PPAR-γ- VSMCs表型转化--VC的作用规律，为VC的防治提供新的方向和靶点。

血管钙化是导致慢性肾衰竭患者心血管事件发生发展的重要危险因素。本课题组结合国内外研究进展以及前期预实验结果，提出环氧二十碳三烯酸（EETs）通过激活过氧化物酶增殖物激活受体γ (PPAR-γ)进而抑制血管平滑肌细胞（VSMCs）表型转化及动脉钙化的假说。在该研究中，我们发现慢性肾衰合并血管钙化的患者其血清中14,15-DHETs的水平显著高于非钙化人群，并且血清中14,15-DHETs的水平与钙化积分具有显著相关性。同时在体及离体实验我们证明Ephx2基因敲除上调内源性EETs水平可以显著抑制VSMCs表型转化及动脉钙化，其机制主要是通过激活PPAR-γ发挥作用。本研究深入剖析了EETs-PPAR-γ-VSMCs表型转化-血管钙化的作用规律，为慢性肾衰患者心血管事件的防治提供了新的治疗策略。