Working model. MI causes ischemia and release of danger signals from dying cells, leading to sequential activation of HIF-2α and then HIF-1α in cardiac macrophages. HIF-2α activates genes involved in fatty acid (FA) synthesis and storage, including HILPDA protein, to antagonize mitochondrial oxidation of FA derived from ACs and anti-inflammatory production of IL-10 by macrophages. HIF-2α also activates inflammatory genes, including Il6, to worsen cardiac repair. In contrast, HIF-1α functions independent of HIF-2α to promote ADAM17-mediated cleavage of MerTK. This results in impaired efferocytosis of apoptotic cardiomyocytes (CM), leading to secondary necrosis and infarct expansion. The cumulative effect is adverse ventricular remodeling and progression to heart failure. Despite their distinct proinflammatory roles, HIFs are also required for cardiac macrophage survival after MI. Loss of both HIF-1α and HIF-2α increases mROS, likely due to reduced expression of antioxidant genes (Pdk1 and Sod2), leading to macrophage necroptosis, impaired scar formation, cardiac rupture, and ultimately, death.