Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac

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-2 alpha, 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-1 alpha and HIF-2 alpha during MI. We found that HIF-2 alpha suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1 alpha promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1 alpha and HIF-2 alpha 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.

Automated summary

This study reveals the significant proinflammatory roles of myeloid cell expression of HIF-1α and HIF-2α during myocardial infarction. While HIF-2α suppresses anti-inflammatory macrophage mitochondrial metabolism, HIF-1α promotes cardioprotective factor MerTK cleavage through glycolytic reprogramming. The combined loss of myeloid HIF-1α and HIF-2α leads to catastrophic consequences, including macrophage necroptosis, impaired fibrogenesis, and cardiac rupture.