Reduction of Circulating Soluble Fms-Like Tyrosine Kinase-1 Plays a Significant Role in Renal Dysfunction-Associated Aggravation of Atherosclerosis
Reduction of Circulating Soluble Fms-Like Tyrosine Kinase-1 Plays a Significant Role in Renal Dysfunction-Associated Aggravation of Atherosclerosis
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DOI：
10.1161/circulationaha.109.867929
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发表时间：
2009-12-15
期刊：
影响因子：
37.8
通讯作者：
Saito, Yoshihiko
中科院分区：
文献类型：
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作者：
Onoue, Kenji;Uemura, Shiro;Saito, Yoshihiko
背景：肾功能不全通常伴随着动脉粥样硬化的恶化；然而，其潜在的分子机制尚不完全清楚。我们研究了可溶性纤维样酪氨酸激酶-1 (sFlt-1)，一种促动脉粥样硬化细胞因子胎盘生长因子（PlGF）的内源性拮抗剂，在肾功能障碍患者和肾功能衰竭动物模型中动脉粥样硬化恶化中的作用。方法与结果：本研究纳入了329例接受心导管插入术的患者和76例接受肾活检的患者。血浆sFlt-1水平和肾脏sFlt-1 mRNA表达与肾小球滤过率呈正相关（P < 0.01）。PlGF/sFlt-1比值与估计的肾小球滤过率呈负相关（P < 0.01），而血浆PlGF水平不受其影响。多支冠状动脉病变患者的PlGF/sFlt-1比值明显高于单支或无冠状动脉病变患者。在五分之六（5/6）肾切除术后出现实验性肾功能障碍的载脂蛋白e缺陷小鼠中，循环sFlt-1和肾脏sFlt-1 mRNA水平的降低得到证实。5/6肾切除的载脂蛋白e缺陷小鼠的动脉粥样硬化斑块面积和巨噬细胞浸润明显高于对照组，但重组sFlt-1替代治疗可显著减少斑块形成和巨噬细胞浸润。结论：目前的研究表明，循环中sFlt-1水平的降低与动脉粥样硬化恶化并伴有肾功能障碍有关。（Circulation. 2009; 120: 2470-2477.）
Background-Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure.Methods and Results-In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (P < 0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P < 0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)-nephrectomized apolipoprotein E-deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6 -nephrectomized apolipoprotein E-deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration.Conclusions-The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction. (Circulation. 2009; 120: 2470-2477.)