Key result
Myeloid HIF-1α and HIF-2α independently antagonize optimal cardiac repair, but their combined loss leads to catastrophic macrophage necroptosis and cardiac rupture.
Why the study?
Although isoform-specific therapeutics are in development for cardiac ischemic injury, the unique role of myeloid HIFs, particularly HIF-2alpha, is unknown.
Myeloid HIF-1α and HIF-2α have unique proinflammatory roles during myocardial infarction, and their combined loss is catastrophic, suggesting a need for selective inhibition of macrophage HIF isoforms to promote ischemic tissue repair.
Selective myeloid HIF inhibition may enhance post-MI repair; leaves open catastrophic rupture risk with dual targeting in ischemic models.
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.
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DeBerge et al. (2021) studied Myocardial infarction. Myeloid cell-specific deletion or overexpression of HIF-1α and HIF-2α vs. Wild-type controls was evaluated on Cardiac remodeling, infarct size, and survival after MI. Myeloid HIF-1α and HIF-2α independently antagonize optimal cardiac repair, but their combined loss leads to catastrophic macrophage necroptosis and cardiac rupture.
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