C1q/TNF-related protein-1: an adipokine marking and promoting atherosclerosis
C1q/TNF-related protein-1: an adipokine marking and promoting atherosclerosis
复制标题
C1q/TNF 相关蛋白-1：脂肪因子标记并促进动脉粥样硬化
DOI：
10.1093/eurheartj/ehv649
复制
发表时间：
2016-06-07
影响因子：
39.3
通讯作者：
Shen, Wei Feng
中科院分区：
文献类型：
--
作者：
Lu, Lin;Zhang, Rui Yan;Shen, Wei Feng
目的探讨脂肪因子C1q/肿瘤坏死因子相关蛋白(CTRP)1与冠状动脉疾病(CAD)的关系及CTRP1的生物学血管效应。方法与结果分析了冠心病患者(n=451例)和非CAD对照组(n=686例)、冠状动脉内膜切除术标本(n=32例)、非动脉粥样硬化性乳内动脉(n=26例)、主动脉粥样硬化斑块(n=15例)和非动脉粥样硬化性主动脉标本(n=10例)的CTRP1水平。冠心病患者血清、动脉内膜切除标本、动脉粥样硬化斑块和外周血单个核细胞(PBMC)中C1q/肿瘤坏死因子相关蛋白水平均高于对照组，且与冠脉病变严重程度相关。CTRP1的产生是由炎性细胞因子诱导的，其本身在人内皮细胞、人外周血单核细胞和THP-1细胞中引起黏附分子和炎性标记物的浓度依赖性表达。C1q/肿瘤坏死因子相关蛋白-1体外诱导p38依赖的单核细胞-内皮细胞黏附和C57BL/6小鼠肠系膜小静脉白细胞募集。动脉粥样硬化的股动脉免疫组织化学显示CD68和VE-钙粘素基因座相关的CTRP1在斑块中的表达增加。与生理盐水相比，隔日腹腔注射重组CTRP1蛋白(200 mg/kg)可促进24周龄apoE(-/-)小鼠动脉粥样硬化的形成。然而，与apoE(-/-)小鼠相比，CTRP1(-/-)/apoE(-/-)双基因敲除小鼠的促动脉粥样硬化作用明显减弱，血管黏附分子、磷酸化p38和肿瘤坏死因子-α的表达持续减少，斑块中巨噬细胞的浸润也持续减少。CTRP-/-小鼠原代培养的内皮细胞和巨噬细胞经肿瘤坏死因子-α诱导的黏附分子和细胞因子的表达明显低于C57BL/6小鼠。结论C1q/肿瘤坏死因子相关蛋白-1是人类动脉粥样硬化的标志物，促进了小鼠动脉粥样硬化的形成。
Aims We investigated the association of the adipokine C1q/TNF-related protein (CTRP) 1 with coronary artery disease (CAD), and the biological vascular effects of CTRP1.Methods and results We analysed CTRP1 levels in sera of CAD patients (n = 451) and non-CAD controls (n = 686), and in coronary endarterectomy specimens (n = 32), non-atherosclerotic internal mammary arteries (n = 26), aortic atherosclerotic plaques (n = 15), and non-atherosclerotic aortic samples (n = 10). C1q/TNF-related protein-levels were higher in sera, endarterectomy specimens, aortic atherosclerotic plaques, and peripheral blood mononuclear cells (PBMCs) from CAD patients compared with controls, and were related to CAD severity. The production of CTRP1 was profusely induced by inflammatory cytokines and itself caused a concentration-dependent expression of adhesion molecules and inflammatory markers in human endothelial cells, human peripheral blood monocytes, and THP-1 cells. C1q/TNF-related protein-1 induced p38-dependent monocyte-endothelium adhesion in vitro and the recruitment of leucocytes to mesenteric venules in C57BL/6 mice. Immunohistochemistry of atherosclerotic femoral arteries exhibited CD68 and VE-cadherin loci-associated increased CTRP1 expression in plaques. Compared with saline, intraperitoneal injection of recombinant CTRP1 protein (200 mg/kg) every other day promoted atherogenesis in apoE(-/-) mice at 24 weeks. However, pro-atherogenic effects were significantly attenuated in CTRP1(-/-)/apoE(-/-) double-knockout mice compared with apoE(-/-) mice, with a consistent decrease in vascular adhesion molecule, phospho-p38 and TNF-alpha expression and macrophage infiltration in plaque in CTRP1(-/-) and double-knockout mice. Tumour necrosis factor-alpha-induced expression of adhesion molecules and cytokines were lower in primary endothelial cells and macrophages from CTRP-/- mice than in those from C57BL/6 mice.Conclusion C1q/TNF-related protein-1 is a marker of atherosclerosis in humans and promotes atherogenesis in mice.