HIF-1α (Hypoxia-Inducible Factor-1α) Promotes Macrophage Necroptosis by Regulating miR-210 and miR-383
HIF-1α (Hypoxia-Inducible Factor-1α) Promotes Macrophage Necroptosis by Regulating miR-210 and miR-383
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DOI：
10.1161/atvbaha.119.313290
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发表时间：
2020-03-01
影响因子：
8.7
通讯作者：
Schober, Andreas
中科院分区：
文献类型：
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作者：
Karshovska, Ela;Wei, Yuanyuan;Schober, Andreas
目的：炎症激活改变了巨噬细胞线粒体的功能，从氧化磷酸化到活性氧的产生，这可能促进了动脉粥样硬化病变中坏死核心的形成。在缺氧和癌细胞中，HIF-1 α（缺氧诱导因子）通过microRNA促进不依赖氧的能量产生。因此，我们研究了HIF-1 α在巨噬细胞能量代谢的调节中的作用，在动脉粥样硬化的背景下。方法和结果：髓细胞特异性删除HIF-1a减少动脉粥样硬化和坏死核心的形成，通过限制载脂蛋白E缺陷小鼠的巨噬细胞坏死凋亡。在炎性骨髓源性巨噬细胞中，Hif 1a的缺失增加了氧化磷酸化、ATP水平和编码线粒体蛋白的基因的表达，并减少了活性氧的产生和坏死性凋亡。microRNA表达谱显示，HIF-1 α上调miR-210，下调miR-383在病变巨噬细胞和炎性骨髓源性巨噬细胞中的水平。与抑制氧化磷酸化和增强线粒体活性氧产生的miR-210相反，miR-383增加ATP水平并抑制坏死性凋亡。miR-210的作用是由于靶向2，4-二烯酰辅酶A还原酶，这是不饱和脂肪酸的β氧化所必需的。miR-383通过靶向聚（ADP-核糖）-糖水解酶（Parg）影响骨髓源性巨噬细胞中的DNA损伤修复途径，从而降低能量消耗并增加细胞存活。通过miR-383阻断Parg的靶向作用，阻止了巨噬细胞中Hif 1a缺失对小鼠动脉粥样硬化和坏死核心形成的保护作用。结论：我们的研究结果揭示了一种新的机制，即炎症巨噬细胞中HIF-1 α的激活通过microRNA介导的ATP耗竭增加坏死性凋亡，从而通过坏死核心形成增加动脉粥样硬化。
Objective:Inflammatory activation changes the mitochondrial function of macrophages from oxidative phosphorylation to reactive oxygen species production, which may promote necrotic core formation in atherosclerotic lesions. In hypoxic and cancer cells, HIF-1 alpha (hypoxia-inducible factor) promotes oxygen-independent energy production by microRNAs. Therefore, we studied the role of HIF-1 alpha in the regulation of macrophage energy metabolism in the context of atherosclerosis.Approach and Results:Myeloid cell-specific deletion of Hif1a reduced atherosclerosis and necrotic core formation by limiting macrophage necroptosis in apolipoprotein E-deficient mice. In inflammatory bone marrow-derived macrophages, deletion of Hif1a increased oxidative phosphorylation, ATP levels, and the expression of genes encoding mitochondrial proteins and reduced reactive oxygen species production and necroptosis. microRNA expression profiling showed that HIF-1 alpha upregulates miR-210 and downregulates miR-383 levels in lesional macrophages and inflammatory bone marrow-derived macrophages. In contrast to miR-210, which inhibited oxidative phosphorylation and enhanced mitochondrial reactive oxygen species production, miR-383 increased ATP levels and inhibited necroptosis. The effect of miR-210 was due to targeting 2,4-dienoyl-CoA reductase, which is essential in the beta oxidation of unsaturated fatty acids. miR-383 affected the DNA damage repair pathway in bone marrow-derived macrophages by targeting poly(ADP-ribose)-glycohydrolase (Parg), which reduced energy consumption and increased cell survival. Blocking the targeting of Parg by miR-383 prevented the protective effect of Hif1a deletion in macrophages on atherosclerosis and necrotic core formation in mice.Conclusions:Our findings unveil a new mechanism by which activation of HIF-1 alpha in inflammatory macrophages increases necroptosis through microRNA-mediated ATP depletion, thus increasing atherosclerosis by necrotic core formation.