Suppressed soluble Fms-like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease
Suppressed soluble Fms-like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease
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DOI：
10.1038/ki.2013.339
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发表时间：
2014-02-01
影响因子：
19.6
通讯作者：
Saito, Yoshihiko
中科院分区：
文献类型：
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作者：
Matsui, Masaru;Takeda, Yukiji;Saito, Yoshihiko
慢性肾脏疾病（CKD）患者死于心血管疾病，原因不明。斑块中血管的形成及其与斑块稳定性的关系可能与Flt-1受体及其配体、血管内皮生长因子以及密切相关的胎盘生长因子（PIGF）的信号传导有关。Flt-1也作为循环调节剪接变异体短抑制形式（sFlt-1）存在，作为诱饵受体，从而使PIGF失活。肝素通过取代硫酸肝素蛋白聚糖中的sFlt-1肝素结合位点释放sFlt-1。肝素可以提供诊断推断，也可以诱导抗血管生成状态。在本研究中，CKD患者的肝素后sFlt-1水平低于对照组。更重要的是，sFlt-1水平与CKD患者的动脉粥样硬化呈负相关，并且在肝素注射后这种相关性更强，这被随后的心血管事件所证实。敲除载脂蛋白E （ApoE）和/或sFlt-1表明，sFlt-1的缺失加重了ApoE缺陷小鼠的动脉粥样硬化。因此，动脉粥样硬化和PIGF信号之间的关系，由sFlt-1调节，强调肝素在sFlt-1释放中的作用被低估。这些临床和实验数据表明，研究ckd依赖性动脉粥样硬化及其检测的新途径是必要的。
Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PIGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PIGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PIGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.