Interferon-γ and the Interferon-Inducible Chemokine CXCL10 Protect Against Aneurysm Formation and Rupture
Interferon-γ and the Interferon-Inducible Chemokine CXCL10 Protect Against Aneurysm Formation and Rupture
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DOI：
10.1161/circulationaha.108.785949
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发表时间：
2009-01-27
期刊：
影响因子：
37.8
通讯作者：
Gerszten, Robert E.
中科院分区：
文献类型：
--
作者：
King, Victoria L.;Lin, Alexander Y.;Gerszten, Robert E.
血管疾病可以表现为狭窄斑块或扩张性动脉瘤，尽管导致这些不同疾病表现的机制仍然知之甚少。辅助性T细胞1型细胞因子，包括干扰素-γ和CXCL 10，有强烈的牵连动脉粥样硬化斑块development.Methods和Results-here，我们特别研究了他们的作用，在血管紧张素II诱导的小鼠模型中的腹主动脉瘤的形成。出乎意料的是，我们发现与Apoe（-/-）对照组相比，载脂蛋白E和干扰素-γ缺陷（Apoe（-/-）/Ifng（-/-））小鼠的肾上主动脉直径、腹主动脉瘤发病率和动脉瘤死亡率增加，尽管动脉粥样硬化管腔斑块形成减弱。在Apoe（-/-）小鼠中，血管紧张素II可高度诱导干扰素-γ诱导的T细胞化学引诱物CXCL 10，但在Apoe（-/-）/Ifng（-/-）小鼠中，这种诱导作用明显减弱。与Apoe（-/-）对照组相比，Apoe（-/-）/Cxcl 10（-/-）小鼠的管腔斑块减少，但主动脉尺寸增加，动脉瘤的形态学分级更差，主动脉破裂导致的死亡发生率更高。此外，Apoe（-/-）/Cxcl 10（-/-）小鼠的腹主动脉瘤富含非辅助性T细胞1型相关信号，包括转化生长因子β 1。治疗Apoe（-/-）/Cxcl 10（-/-）小鼠与抗转化生长因子β中和抗体减少血管紧张素II诱导的aortic dilatation. Conclusions-本研究定义了一种新的途径，其中干扰素-γ及其效应器，CXCL 10，有助于不同的途径在腹主动脉瘤与斑块形成，抑制前者的病理，但促进后者。因此，努力发展动脉粥样硬化的治疗策略必须仔细考虑对血管疾病所有表现的潜在影响。（循环。2009; 119：426-435）。
Background-Vascular disease can manifest as stenotic plaques or ectatic aneurysms, although the mechanisms culminating in these divergent disease manifestations remain poorly understood. T-helper type 1 cytokines, including interferon-gamma and CXCL10, have been strongly implicated in atherosclerotic plaque development.Methods and Results-Here, we specifically examined their role in the formation of abdominal aortic aneurysms in the angiotensin II-induced murine model. Unexpectedly, we found increased suprarenal aortic diameters, abdominal aortic aneurysm incidence, and aneurysmal death in apolipoprotein E- and interferon-gamma-deficient (Apoe(-/-)/Ifng(-/-)) mice compared with Apoe(-/-) controls, although atherosclerotic luminal plaque formation was attenuated. The interferon-gamma-inducible T-cell chemoattractant CXCL10 was highly induced by angiotensin II infusion in Apoe(-/-) mice, but this induction was markedly attenuated in Apoe(-/-)/Ifng(-/-) mice. Apoe(-/-)/Cxcl10(-/-) mice had decreased luminal plaque but also increased aortic size, worse morphological grades of aneurysms, and a higher incidence of death due to aortic rupture than Apoe(-/-) controls. Furthermore, abdominal aortic aneurysms in Apoe(-/-)/Cxcl10(-/-) mice were enriched for non-T-helper type 1-related signals, including transforming growth factor-beta 1. Treatment of Apoe(-/-)/Cxcl10(-/-) mice with anti-transforming growth factor-beta neutralizing antibody diminished angiotensin II-induced aortic dilation.Conclusions-The present study defines a novel pathway in which interferon-gamma and its effector, CXCL10, contribute to divergent pathways in abdominal aortic aneurysm versus plaque formation, inhibiting the former pathology but promoting the latter. Thus, efforts to develop antiinflammatory strategies for atherosclerosis must carefully consider potential effects on all manifestations of vascular disease. (Circulation. 2009; 119: 426-435.)