Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension.
Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension.
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DOI：
10.1096/fj.201500088r
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发表时间：
2016-05
期刊：
影响因子：
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通讯作者：
Guzik TJ
中科院分区：
文献类型：
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作者：
Mikolajczyk TP;Nosalski R;Szczepaniak P;Budzyn K;Osmenda G;Skiba D;Sagan A;Wu J;Vinh A;Marvar PJ;Guzik B;Podolec J;Drummond G;Lob HE;Harrison DG;Guzik TJ
最近的研究强调了血管周围炎症在心血管疾病中的作用。我们研究了血管紧张素II（Ang II）诱导的高血压血管周围白细胞浸润的机制及其与血管功能障碍的联系。长期输注Ang II可增加小鼠血管周围脂肪组织中T细胞（255 ± 130至1664 ± 349个细胞/mg; P < 0.01）、M1和M2巨噬细胞以及树突状细胞的免疫细胞含量。特别是，Ang II增加了携带RANTES趋化因子受体CC趋化因子受体（CCR）1、CCR 3和CCR 5的T淋巴细胞的含量（CCR 1，15.6 ± 1.5%对31 ± 5%; P < 0.01）。高血压与血管周围脂肪组织中趋化因子RANTES表达的增加相关（相对定量，1.2 ± 0.2 vs. 3.5 ± 1.1; P < 0.05），其诱导T细胞趋化性和表达趋化因子受体CCR 1、CCR 3和CCR 5的T细胞的血管积聚。从机制上讲，RANTES−/−敲除可保护血管白细胞，特别是T淋巴细胞浸润（野生型Ang II为26 ± 5%，RANTES−/−为15 ± 4%），这与保护血管内皮细胞免受Ang II诱导的内皮功能障碍有关。这种效应与产生IFN-γ的CD 8+和双阴性CD 3 + CD 4 − CD 8 − T细胞在血管周围空间的浸润减少以及血管氧化应激减少有关，而FoxP 3 + T调节细胞没有改变。IFN-γ离体引起显著的内皮功能障碍，其通过超氧阴离子清除而减轻。在一个人类队列中，作为生物标志物的循环RANTES水平与测量为血流介导的扩张（R =-0.3，P < 0.01）或内皮损伤标志物血管性血友病因子（R = +0.3，P < 0.01）的血管功能之间存在显著的负相关性。因此，趋化因子RANTES在通过调节血管周围炎症来调节血管功能障碍中是重要的。Mikolajczyk，T. P.的人，诺萨尔斯基河Szczepaniak，P.，布津，K.，Osmenda，G.，Skiba，D.，Sagan，A.，吴，J.，Vinh，A.，Marvar，P. J.，Guzik，B.，Podolec，J.，德拉蒙德，G.，Lob，H. E、哈里森，D。G.，Guzik，T.趋化因子RANTES在高血压血管周围炎症、T细胞积聚和血管功能障碍的调节中的作用。
Recent studies have emphasized the role of perivascular inflammation in cardiovascular disease. We studied mechanisms of perivascular leukocyte infiltration in angiotensin II (Ang II)-induced hypertension and their links to vascular dysfunction. Chronic Ang II infusion in mice increased immune cell content of T cells (255 ± 130 to 1664 ± 349 cells/mg; P < 0.01), M1 and M2 macrophages, and dendritic cells in perivascular adipose tissue. In particular, the content of T lymphocytes bearing CC chemokine receptor (CCR) 1, CCR3, and CCR5 receptors for RANTES chemokine was increased by Ang II (CCR1, 15.6 ± 1.5% vs. 31 ± 5%; P < 0.01). Hypertension was associated with an increase in perivascular adipose tissue expression of the chemokine RANTES (relative quantification, 1.2 ± 0.2 vs. 3.5 ± 1.1; P < 0.05), which induced T-cell chemotaxis and vascular accumulation of T cells expressing the chemokine receptors CCR1, CCR3, and CCR5. Mechanistically, RANTES−/− knockout protected against vascular leukocyte, and in particular T lymphocyte infiltration (26 ± 5% in wild type Ang II vs. 15 ± 4% in RANTES−/−), which was associated with protection from endothelial dysfunction induced by Ang II. This effect was linked with diminished infiltration of IFN-γ-producing CD8+ and double-negative CD3+CD4−CD8− T cells in perivascular space and reduced vascular oxidative stress while FoxP3+ T-regulatory cells were unaltered. IFN-γ ex vivo caused significant endothelial dysfunction, which was reduced by superoxide anion scavenging. In a human cohort, a significant inverse correlation was observed between circulating RANTES levels as a biomarker and vascular function measured as flow-mediated dilatation (R = −0.3, P < 0.01) or endothelial injury marker von Willebrand factor (R = +0.3; P < 0.01). Thus, chemokine RANTES is important in the regulation of vascular dysfunction through modulation of perivascular inflammation.—Mikolajczyk, T. P., Nosalski, R., Szczepaniak, P., Budzyn, K., Osmenda, G., Skiba, D., Sagan, A., Wu, J., Vinh, A., Marvar, P. J., Guzik, B., Podolec, J., Drummond, G., Lob, H. E., Harrison, D. G., Guzik, T. J. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension.