| First Author | DeBerge M | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 9 | PubMed ID | 34325467 |
| Mgi Jnum | J:321683 | Mgi Id | MGI:6887329 |
| Doi | 10.1084/jem.20200667 | Citation | DeBerge M, et al. (2021) Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair. J Exp Med 218(9):e20200667 |
| abstractText | 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-2alpha, 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-1alpha and HIF-2alpha during MI. We found that HIF-2alpha suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1alpha promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1alpha and HIF-2alpha 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. |
