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Elucidation of the arteriosclerosis control mechanism of soluble Flt-1 in the renal insufficiency

阐明可溶性Flt-1在肾功能不全中的动脉硬化控制机制

基本信息

批准号：
22790722
负责人：
TAKEDA Yukiji
金额：
$ 2.58万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790722/
关键词：
分子心臓病態学 sFlt-1 慢性腎不全可溶性Flt-1 腎不全動脈硬化マクロファージ

项目摘要

Placental growth factor(PlGF), a family of VEGF, plays important roles in the development of atherosclerosis, which is antagonized by sFlt-1.In our study, plasma sFlt-1 level was positively correlated with eGFR in the 329 patients underwent cardiac catheterization(after 20-Unit heparin administration). The PlGF/sFlt-1 ratio was significantly correlated with multi-vessel coronary artery disease.Heparin is reported to affect on plasma sFlt-1 level, we have to consider the effect of heparin during the cardiac catheterization. We hypothesized that the heparin-induced increment of plasma sFlt-1 level would indicate the total circulating sFlt-1 and systemic release from endothelial cells. Plasma sFlt-1 levels increased in 251 CKD patients after heparin injection(0.4IU/Kg) and that the level was positively correlated with eGFR, though the effect is opposite in baseline circulating sFlt-1 level. Mice study also revealed that sFlt-1 mRNA expression in organs examined(kidney, lung) was suppressed by about 50% in 5/6 nephrectomized mice, indicating total amount of sFlt-1 was decreased in CKD.Analysis of 343 CKD patients revealed that patients with higher PlGF/sFlt-1 ratio after heparin injection had significantly higher risk of acute cardiac death plus total cardiovascular event compared to lower ratio.Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly increased in 5/6 nephrectomized ApoE-deficient mice ; a model of atherosclerosis in renal failure. Replacement therapy with recombinant sFlt-1 significantly reduced atherosclerotic plaque formation.PlGF/sFlt-1 has an important role in atherosclerotic process of CKD patients.

胎盘生长因子（PlGF）是血管内皮生长因子（VEGF）家族成员之一，在动脉粥样硬化的发生发展中起重要作用，sFlt-1可拮抗PlGF的作用。PlGF/sFlt-1比值与多支冠状动脉病变密切相关，肝素可影响血浆sFlt-1水平，在心导管术中应考虑肝素的影响。我们假设肝素诱导的血浆sFlt-1水平的增加将指示从内皮细胞的总循环sFlt-1和全身释放。251例CKD患者注射肝素（0.4IU/Kg）后血浆sFlt-1水平升高，且与eGFR呈正相关，而基线循环sFlt-1水平则相反。小鼠研究还显示，sFlt-1 mRNA在所检查的器官中的表达（肾，肺）在5/6肾切除小鼠中被抑制约50%，对343例CKD患者的分析显示，PlGF/sFlt-1较高的患者，肝素注射后的比率1与较低比率相比，急性心源性死亡和总心血管事件的风险显著更高。在5/6肾切除的ApoE缺陷小鼠（肾衰竭中的动脉粥样硬化模型）中，斑块面积和巨噬细胞浸润到斑块中显著增加。重组sFlt-1替代治疗可显著减少CKD患者动脉粥样硬化斑块的形成，PlGF/sFlt-1在CKD患者动脉粥样硬化过程中起重要作用。