Annemarie Aarup1, Tanja X Pedersen1, Nanna Junker1, Christina Christoffersen1, Emil D Bartels1, Marie Madsen1, Carsten H Nielsen1, Lars B Nielsen2. 1. From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.). 2. From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.). lars.bo.nielsen@regionh.dk.
Abstract
OBJECTIVE: Atherosclerotic lesions contain hypoxic areas, but the pathophysiological importance of hypoxia is unknown. Hypoxia-inducible factor-1α (HIF-1α) is a key transcription factor in cellular responses to hypoxia. We investigated the hypothesis that HIF-1α 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-1α-expressing macrophages in murine atherosclerotic lesions. To investigate the significance of macrophage HIF-1α, Ldlr(-/-) mice were transplanted with bone marrow from mice with HIF-1α deficiency in the myeloid cells or control bone marrow. The HIF-1α deficiency in myeloid cells reduced atherosclerosis in aorta of the Ldlr(-/-) recipient mice by ≈72% (P=0.006).In vitro, HIF-1α-deficient macrophages displayed decreased differentiation to proinflammatory M1 macrophages and reduced expression of inflammatory genes. HIF-1α deficiency also affected glucose uptake, apoptosis, and migratory abilities of the macrophages. CONCLUSIONS: HIF-1α expression in macrophages affects their intrinsic inflammatory profile and promotes development of atherosclerosis.
OBJECTIVE:Atherosclerotic lesions contain hypoxic areas, but the pathophysiological importance of hypoxia is unknown. Hypoxia-inducible factor-1α (HIF-1α) is a key transcription factor in cellular responses to hypoxia. We investigated the hypothesis that HIF-1α 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-1α-expressing macrophages in murineatherosclerotic lesions. To investigate the significance of macrophage HIF-1α, Ldlr(-/-) mice were transplanted with bone marrow from mice with HIF-1α deficiency in the myeloid cells or control bone marrow. The HIF-1α deficiency in myeloid cells reduced atherosclerosis in aorta of the Ldlr(-/-) recipient mice by ≈72% (P=0.006).In vitro, HIF-1α-deficient macrophages displayed decreased differentiation to proinflammatory M1 macrophages and reduced expression of inflammatory genes. HIF-1α deficiency also affected glucose uptake, apoptosis, and migratory abilities of the macrophages. CONCLUSIONS: HIF-1α expression in macrophages affects their intrinsic inflammatory profile and promotes development of atherosclerosis.
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