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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 36; no. 9; pp. 1782 - 1790
• Main Authors: Aarup, Annemarie, Pedersen, Tanja X, Junker, Nanna, Christoffersen, Christina, Bartels, Emil D, Madsen, Marie, Nielsen, Carsten H, Nielsen, Lars B
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.09.2016
• Subjects: Animals; Aorta, Thoracic - metabolism; Aorta, Thoracic - pathology; Aortic Diseases - genetics; Aortic Diseases - metabolism; Aortic Diseases - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Apoptosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Bone Marrow Transplantation; Cell Differentiation; Cell Hypoxia; Cell Movement; Cells, Cultured; Cholesterol - metabolism; Disease Models, Animal; Disease Progression; Foam Cells - metabolism; Foam Cells - pathology; Genetic Predisposition to Disease; Glucose - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - deficiency; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inflammation Mediators - metabolism; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Plaque, Atherosclerotic; Receptors, LDL - deficiency; Receptors, LDL - genetics; Signal Transduction; atherosclerosis; hypoxia-inducible factor 1α; hypoxia; apoptosis; macrophage
• DOI: 10.1161/ATVBAHA.116.307830
• ISSN: 1079-5642

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.