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.

Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

“…As mentioned, MLN4924 increases LPSinduced HIF-1α levels in endothelial cells, which corresponds with a previous observation of increased HIF activity in the kidney of LPS-treated mice (26). Interestingly, endothelial HIF-1α had been found to promote atherosclerosis and enhance leukocyte adhesion, and myeloid HIF-1α was seen to promote or not affect atherosclerotic lesion formation (60,72,73). With respect to our study, this could imply that increased HIF-1α may begin to counteract initial NF-κB-associated atheroprotective effects of MLN4924 implicated in early atherosclerosis and explain the absence of atheroprotection in more advanced lesions.…”

Reactive Oxygen Species Generation and Atherosclerosis

“…4,83,84 At the beginning of atherosclerosis, monocytes, which are attracted by the chemokines secreted by resident vascular cells, migrate into the subendothelial area where they differentiate into macrophages on growth factors stimulation. 83 In the atherosclerotic lesions, macrophages ingest oxidized LDL through scavenger receptors and become lipid-laden foam cells.…”

Macrophages

“…47,48 Hypoxia promotes glucose uptake by macrophages and potentiates glycolysis in parallel with the development of a proinflammatory M1 phenotype (essentially increased NOS2), dependent on HIF1α expression and 6-phosphofructo-2-kinase. 47,49 Deletion of HIF1α in murine myeloid cells (granulocytes and macrophages) does not affect the development of early atherosclerotic lesions 48 but significantly limits the accumulation of M1-like macrophages and reduces the development of advanced atherosclerosis. 47 This contrasts with the role of HIF1α in CD11c + antigen-presenting cells where it seems to limit proatherogenic Th1 cells through STAT3-dependent inhibition of interleukin-12 (IL-12) production.…”

“…47,49 Deletion of HIF1α in murine myeloid cells (granulocytes and macrophages) does not affect the development of early atherosclerotic lesions 48 but significantly limits the accumulation of M1-like macrophages and reduces the development of advanced atherosclerosis. 47 This contrasts with the role of HIF1α in CD11c + antigen-presenting cells where it seems to limit proatherogenic Th1 cells through STAT3-dependent inhibition of interleukin-12 (IL-12) production. 48 In another study, inhibition of HIF-inducible prolyl 4-hydroxylase-2 in HIF-P4H-2-hypomorphic/C699Y-Ldlr −/− mice or using an oral small molecule inhibitor induced a stabilization of HIF1α and HIF2α and led to a reduction of atherosclerosis.…”