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

胎盘生长因子(PlGF)是血管内皮细胞生长因子家族中的一个家族，在动脉粥样硬化的发生发展中起重要作用，而sFlt-1可拮抗胎盘生长因子的作用。PlGF/sFlt-1比值与多支冠状动脉病变密切相关，肝素对血浆sFlt-1水平有影响，在心导管术中需考虑肝素的影响。我们推测，肝素诱导的血浆sFlt-1水平的升高可能表明循环中sFlt-1的总水平和血管内皮细胞的全身释放。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，而基础循环sFlt-1水平则相反。小鼠研究还发现，在5/6肾切除小鼠中，被检查的器官(肾脏、肺)中sFlt-1mRNA的表达被抑制了约50%，表明CKD中sFlt-1的总量减少。对343例CKD患者的分析表明，注射肝素后PlGF/sFlt-1比率较高的患者发生急性心脏性死亡和总心血管事件的风险显著高于比率较低的患者。5/6肾切除ApoE缺陷小鼠的动脉粥样硬化斑块面积和巨噬细胞渗入斑块的风险显著增加；重组sFlt-1替代治疗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.