CTRP5 promotes transcytosis and oxidative modification of low-density lipoprotein and the development of atherosclerosis
CTRP5 promotes transcytosis and oxidative modification of low-density lipoprotein and the development of atherosclerosis
复制标题
CTRP5促进低密度脂蛋白的转胞吞作用和氧化修饰以及动脉粥样硬化的发展
DOI：
10.1016/j.atherosclerosis.2018.09.037
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发表时间：
2018-11-01
期刊：
影响因子：
5.3
通讯作者：
Lu, Lin
中科院分区：
文献类型：
--
作者：
Li, Chang;Chen, Jia Wei;Lu, Lin
背景和目的：低密度脂蛋白(低密度脂蛋白)跨内皮细胞转运增加和内皮下间隙内低密度脂蛋白氧化是动脉粥样硬化形成的重要早期事件。CL-Q/肿瘤坏死因子相关蛋白(CTRP)5是一种新的分泌型糖蛋白，其生物学功能尚未明确。方法：分析CTRP5在冠心病患者血清和动脉粥样硬化斑块中的表达。结果：冠心病组患者血清CTRP5水平明显高于非冠心病组(247.26±61.71vs.167.81+/-68.08 ng/mL，p<；0.001)，且与病变血管数呈正相关(Spearman‘s r=0.611，p<；0.001)。CTRP5在人冠状动脉内膜剥脱术标本中的表达高于非动脉粥样硬化动脉。免疫荧光进一步显示CTRP5主要定位于新生内膜的内皮细胞、浸润性巨噬细胞和平滑肌细胞。体内和体外实验表明，CTRP5可促进低密度脂蛋白跨内皮单分子层的细胞穿透，以及内皮细胞内低密度脂蛋白的氧化修饰。在机制上，我们发现CTRP5通过STAT6信号上调了12/15-脂氧合酶(LOX)，LOX是介导低密度脂蛋白运输和氧化的关键酶。结论：CTRP5是一种新的促动脉粥样硬化的细胞因子，通过上调12/15-LOX的表达，促进内皮细胞内低密度脂蛋白的跨细胞转运和氧化。
Background and aims: Increased transcytosis of low-density lipoprotein (LDL) across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. Cl q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined.Methods: Expression of CTRP5 was analyzed in sera and atherosclerotic plaques of patients with coronary artery disease (CAD). The role of CTRP5 in atherogenesis was investigated in vitro and in vivo.Results: We found CTRP5 serum levels were higher in patients with than without CAD (247.26 +/- 61.71 vs. 167.81 +/- 68.08 ng/mL, p < 0.001), and were positively correlated with the number of diseased vessels (Spearman's r = 0.611, p < 0.001). Increased expression of CTRP5 was detected in human coronary endarterectomy specimens as compared to non-atherosclerotic arteries. Immunofluorescence further showed that CTRP5 was predominantly localized in the endothelium, infiltrated macrophages and smooth muscle cells in the neointima. In vivo and in vitro experiments demonstrated that CTRP5 promoted transcytosis of LDL across endothelial monolayers, as well as the oxidative modification of LDL in endothelial cells. Mechanistically, we found that CTRP5 up-regulated 12/15-lipoxygenase (LOX), a key enzyme in mediating LDL trafficking and oxidation, through STAT6 signaling. Genetic or pharmacological inhibition of 12/15-LOX dramatically attenuated the deposition of oxidized LDL in the subendothelial space and the development of atherosclerosis.Conclusions: These data indicate that CTRP5 is a novel pro-atherogenic cytokine and promotes transcytosis and oxidation of LDL in endothelial cells via up-regulation of 12/15-LOX.