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-1α (hypoxia-inducible factor) promotes oxygen-independent energy production by microRNAs. Therefore, we studied the role of HIF-1α 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-1α 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 β 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-1α in inflammatory macrophages increases necroptosis through microRNA-mediated ATP depletion, thus increasing atherosclerosis by necrotic core formation.

中文翻译：

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HIF-1α（缺氧诱导因子-1α）通过调节miR-210和miR-383促进巨噬细胞坏死性硬化。

目的炎症激活将巨噬细胞的线粒体功能从氧化磷酸化转变为活性氧的产生，这可能会促进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-1α（低氧诱导因子）可促进microRNA产生不依赖氧的能量。因此，我们研究了在动脉粥样硬化的背景下，HIF-1α在巨噬细胞能量代谢调节中的作用。方法和结果：通过限制载脂蛋白E缺乏症小鼠的巨噬细胞坏死性病变，Hif1a的髓样细胞特异性缺失减少了动脉粥样硬化和坏死性核心形成。在炎症性骨髓衍生的巨噬细胞中，Hif1a的缺失会增加氧化磷酸化，ATP水平，以及编码线粒体蛋白的基因的表达，减少了活性氧的产生和坏死。microRNA表达谱显示，HIF-1α在病变巨噬细胞和炎症性骨髓衍生巨噬细胞中上调miR-210和下调miR-383水平。与抑制氧化磷酸化和增强线粒体活性氧生成的miR-210相反，miR-383增加ATP含量并抑制坏死性坏死。miR-210的作用归因于靶向2，4-二烯酰基-CoA还原酶，这在不饱和脂肪酸的β氧化中必不可少。miR-383通过靶向聚（ADP-核糖）-糖基水解酶（Parg）来影响骨髓源巨噬细胞的DNA损伤修复途径，从而减少了能量消耗并提高了细胞存活率。miR-383阻止Parg的靶向作用，阻止了巨噬细胞中Hif1a缺失对小鼠动脉粥样硬化和坏死核心形成的保护作用。结论我们的发现揭示了一种新的机制，通过该机制，炎症巨噬细胞中HIF-1α的激活通过microRNA介导的ATP耗竭增加了坏死性硬化，从而通过坏死性核心形成而增加了动脉粥样硬化。