Hypoxia-Inducible Factor-1 Expression in Macrophages Promotes Development of Atherosclerosis

Objective Atherosclerotic lesions contain hypoxic areas, but the pathophysiological importance of hypoxia is unknown. Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in cellular responses to hypoxia. We investigated the hypothesis that HIF-1 has effects on macrophage biology that promotes atherogenesis in mice. Approach and Results Studies with molecular probes, immunostaining, and laser microdissection of aortas revealed abundant hypoxic, HIF-1-expressing macrophages in murine atherosclerotic lesions. To investigate the significance of macrophage HIF-1, Ldlr(-/-) mice were transplanted with bone marrow from mice with HIF-1 deficiency in the myeloid cells or control bone marrow. The HIF-1 deficiency in myeloid cells reduced atherosclerosis in aorta of the Ldlr(-/-) recipient mice by approximate to 72% (P=0.006). In vitro, HIF-1-deficient macrophages displayed decreased differentiation to proinflammatory M1 macrophages and reduced expression of inflammatory genes. HIF-1 deficiency also affected glucose uptake, apoptosis, and migratory abilities of the macrophages. Conclusions HIF-1 expression in macrophages affects their intrinsic inflammatory profile and promotes development of atherosclerosis.