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

Annemarie Aarup; Tanja X Pedersen; Nanna Junker; Christina Christoffersen; Emil D Bartels; Marie Madsen; Carsten H Nielsen; Lars B Nielsen

doi:10.1161/ATVBAHA.116.307830

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

Annemarie Aarup, Tanja X Pedersen, Nanna Junker, Christina Christoffersen, Emil D Bartels, Marie Madsen, Carsten H Nielsen, Lars B Nielsen

Department of Clinical Biochemistry

117 Citations (Scopus)

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.

Original language	English
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
Volume	36
Issue number	9
Pages (from-to)	1782-90
Number of pages	9
ISSN	1079-5642
DOIs	https://doi.org/10.1161/ATVBAHA.116.307830
Publication status	Published - Sept 2016

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Journal Article

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10.1161/ATVBAHA.116.307830

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title = "Hypoxia-Inducible Factor-1α Expression in Macrophages Promotes Development of Atherosclerosis",

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.",

keywords = "Journal Article",

author = "Annemarie Aarup and Pedersen, {Tanja X} and Nanna Junker and Christina Christoffersen and Bartels, {Emil D} and Marie Madsen and Nielsen, {Carsten H} and Nielsen, {Lars B}",

note = "{\textcopyright} 2016 American Heart Association, Inc.",

year = "2016",

month = sep,

doi = "10.1161/ATVBAHA.116.307830",

language = "English",

volume = "36",

pages = "1782--90",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

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T1 - Hypoxia-Inducible Factor-1α Expression in Macrophages Promotes Development of Atherosclerosis

AU - Aarup, Annemarie

AU - Pedersen, Tanja X

AU - Junker, Nanna

AU - Christoffersen, Christina

AU - Bartels, Emil D

AU - Madsen, Marie

AU - Nielsen, Carsten H

AU - Nielsen, Lars B

PY - 2016/9

Y1 - 2016/9

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1161/ATVBAHA.116.307830

DO - 10.1161/ATVBAHA.116.307830

M3 - Journal article

C2 - 27444197

SN - 1079-5642

VL - 36

SP - 1782

EP - 1790

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 9

ER -

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

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