Inteirferon-α promotes abnormal vasculogenesis in lupus:: a potential pathway for premature atherosclerosis
Inteirferon-α promotes abnormal vasculogenesis in lupus:: a potential pathway for premature atherosclerosis
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DOI：
10.1182/blood-2007-05-089086
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发表时间：
2007-10-15
期刊：
影响因子：
20.3
通讯作者：
Kaplan, Mariana J.
中科院分区：
文献类型：
--
作者：
Denny, Michael F.;Thacker, Seth;Kaplan, Mariana J.
系统性红斑狼疮(SLE)患者病因不明的早发性动脉粥样硬化显著增加。系统性红斑狼疮患者内皮细胞凋亡加速，并与内皮功能障碍密切相关。血管损伤后，内皮祖细胞和单核细胞循环血管生成细胞在血管修复中起着至关重要的作用，内皮祖细胞/血管生成细胞水平降低或功能异常是动脉粥样硬化的危险因素。我们调查了系统性红斑狼疮患者血管修复是否受损。我们报告SLE患者表现出异常的EPC/CACs表型和功能。这些异常的特点是循环内皮祖细胞数量显著减少(SLE组为310+/-50个/毫升血，对照组为639+/-102个/毫升)，并且EPC/CACs分化为成熟内皮细胞并合成足够水平的前血管生成分子血管内皮生长因子(VEGF)和肝生长因子(HGF)的能力显著受损。这些异常是由干扰素-α(干扰素-α)触发的，干扰素-α诱导EPC和CAC凋亡，并使髓系细胞向非血管生成表型倾斜。狼疮内皮祖细胞/CACs增加了干扰素-α的表达，其上清液促进了干扰素诱导基因的更高诱导。重要的是，中和干扰素途径可以恢复狼疮患者正常的EPC/CAC表型。系统性红斑狼疮的特点是由I型干扰素引起的内皮细胞损伤和修复之间的失衡，这可能会促进动脉粥样硬化的加速。
Individuals with systemic lupus erythematosus (SLE) have a striking increase in premature atherosclerosis of unclear etiology. Accelerated endothelial cell apoptosis occurs in SLE and correlates with endothelial dysfunction. Endothelial progenitor cells (EPCs) and myelomonocytic circulating angiogenic cells (CACs) are crucial in blood vessel repair after vascular damage, and decreased levels or abnormal function of EPCs/CACs are established atherosclerosis risk factors. We investigated if vascular repair is impaired in SLE. We report that SLE patients display abnormal phenotype and function of EPCs/CACs. These abnormalities are characterized by significant decreases in the number of circulating EPCs (310 +/- 50 EPCs/mL of blood in SLE versus 639 +/- 102 in controls) and significant impairments in the capacity of EPCs/CACs to differentiate into mature ECs and synthesize adequate levels of the proangiogenic molecules vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF). These abnormalities are triggered by interferon-alpha (IFN-alpha), which induces EPC and CAC apoptosis and skews myeloid cells toward nonangiogenic phenotypes. Lupus EPCs/CACs have increased IFN-alpha expression and their supernatants promote higher induction of IFN-Inducible genes. Importantly, neutralization of IFN pathways restores a normal EPC/CAC phenotype in lupus. SLE is characterized by an imbalance between endothelial cell damage and repair triggered by type I IFNs, which might promote accelerated atherosclerosis.