Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.

中文翻译：

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缺氧诱导因子单独促进炎症骨髓代谢和低效心脏修复

缺氧诱导因子 (HIF) 在实质细胞中响应低氧而被激活，因此已被提议作为缺氧损伤期间的治疗靶点，包括心肌梗塞 (MI)。HIF 也会在巨噬细胞内被激活，从而协调组织修复反应。尽管针对心脏缺血性损伤的异构体特异性疗法正在开发中，但令人惊讶的是，骨髓 HIF（尤其是 HIF-2α）的独特作用尚不清楚。使用心肌梗死小鼠模型和条件性遗传丧失和功能获得的小鼠，我们发现了 MI 期间骨髓细胞表达 HIF-1α 和 HIF-2α 的独特促炎作用。我们发现 HIF-2α 抑制抗炎巨噬细胞线粒体代谢，而 HIF-1α 通过巨噬细胞的糖酵解重编程促进心脏保护性 MerTK 的裂解。出乎意料的是，骨髓 HIF-1α 和 HIF-2α 的组合损失是灾难性的，导致巨噬细胞坏死性凋亡、纤维发生受损和心脏破裂。这些发现支持在缺血组织修复过程中选择性抑制巨噬细胞 HIF 亚型并促进抗炎线粒体代谢的策略。