Hypoxia-Inducible Factor-1 Expression in Macrophages Promotes Development of Atherosclerosis
Hypoxia-Inducible Factor-1 Expression in Macrophages Promotes Development of Atherosclerosis
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DOI：
10.1161/atvbaha.116.307830
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发表时间：
2016-09-01
影响因子：
8.7
通讯作者：
Nielsen, Lars B.
中科院分区：
文献类型：
--
作者：
Aarup, Annemarie;Pedersen, Tanja X.;Nielsen, Lars B.
目的动脉粥样硬化病变含有缺氧区域，但缺氧的病理生理学重要性尚不清楚。缺氧诱导因子-1 (HIF-1) 是细胞对缺氧反应的关键转录因子。我们研究了 HIF-1 对促进小鼠动脉粥样硬化形成的巨噬细胞生物学有影响的假设。方法和结果通过分子探针、免疫染色和主动脉激光显微切割进行的研究揭示了小鼠动脉粥样硬化病变中存在丰富的缺氧、表达 HIF-1 的巨噬细胞。为了研究巨噬细胞HIF-1的意义，Ldlr(-/-)小鼠被移植了骨髓细胞中HIF-1缺陷的小鼠或对照骨髓的骨髓。骨髓细胞中的HIF-1缺陷使Ldlr(-/-)受体小鼠的主动脉粥样硬化减少了约72%（P=0.006）。在体外，HIF-1缺陷型巨噬细胞向促炎性M1巨噬细胞的分化能力降低，并且炎症基因的表达降低。 HIF-1缺乏还影响巨噬细胞的葡萄糖摄取、细胞凋亡和迁移能力。结论巨噬细胞中HIF-1的表达影响其内在炎症特征并促进动脉粥样硬化的发展。
Objective Atherosclerotic lesions contain hypoxic areas, but the pathophysiological importance of hypoxia is unknown. Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in cellular responses to hypoxia. We investigated the hypothesis that HIF-1 has effects on macrophage biology that promotes atherogenesis in mice.Approach and Results Studies with molecular probes, immunostaining, and laser microdissection of aortas revealed abundant hypoxic, HIF-1-expressing macrophages in murine atherosclerotic lesions. To investigate the significance of macrophage HIF-1, Ldlr(-/-) mice were transplanted with bone marrow from mice with HIF-1 deficiency in the myeloid cells or control bone marrow. The HIF-1 deficiency in myeloid cells reduced atherosclerosis in aorta of the Ldlr(-/-) recipient mice by approximate to 72% (P=0.006). In vitro, HIF-1-deficient macrophages displayed decreased differentiation to proinflammatory M1 macrophages and reduced expression of inflammatory genes. HIF-1 deficiency also affected glucose uptake, apoptosis, and migratory abilities of the macrophages.Conclusions HIF-1 expression in macrophages affects their intrinsic inflammatory profile and promotes development of atherosclerosis.