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

胎盘生长因子（PlGF）是VEGF家族的一员，在动脉粥样硬化的发生发展中起重要作用，可被sFlt-1拮抗。在我们的研究中，329例心导管患者（给予20单位肝素后）血浆sFlt-1水平与eGFR呈正相关。PlGF/sFlt-1比值与多支冠状动脉病变有显著相关性。肝素有影响血浆sFlt-1水平的报道，我们必须考虑肝素在心导管插入术中的作用。我们假设肝素诱导的血浆sFlt-1水平升高表明内皮细胞的循环sFlt-1总量和全身释放。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，但与基线循环sFlt-1水平相反。小鼠研究还发现，在5/6肾切除小鼠中，sFlt-1 mRNA在检查器官（肾、肺）中的表达被抑制了约50%，表明CKD中sFlt-1的总量减少。对343例CKD患者的分析显示，注射肝素后PlGF/sFlt-1比值较高的患者发生急性心源性死亡和总心血管事件的风险明显高于比值较低的患者。5/6肾切除apoe缺陷小鼠动脉粥样硬化斑块面积和斑块内巨噬细胞浸润显著增加；肾功能衰竭的动脉粥样硬化模型。重组sFlt-1替代疗法可显著减少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发挥重要作用。

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.