In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. 11 ( 2015-11), p. 2316-2325
Abstract:
Although immune responses drive the pathogenesis of atherosclerosis, mechanisms that control antigen-presenting cell (APC)–mediated immune activation in atherosclerosis remain elusive. We here investigated the function of hypoxia-inducible factor (HIF)-1α in APCs in atherosclerosis. Approach and Results— We found upregulated HIF1α expression in CD11c + APCs within atherosclerotic plaques of low-density lipoprotein receptor–deficient ( Ldlr −/− ) mice. Conditional deletion of Hif1a in CD11c + APCs in high-fat diet–fed Ldlr −/− mice accelerated atherosclerotic plaque formation and increased lesional T-cell infiltrates, revealing a protective role of this transcription factor. HIF1α directly controls Signal Transducers and Activators of Transcription 3 ( Stat3 ), and a reduced STAT3 expression was found in HIF1α-deficient APCs and aortic tissue, together with an upregulated interleukin-12 expression and expansion of type 1 T-helper (Th1) cells. Overexpression of STAT3 in Hif1a -deficient APCs in bone marrow reversed enhanced atherosclerotic lesion formation and reduced Th1 cell expansion in chimeric Ldlr −/− mice. Notably, deletion of Hif1a in LysM + bone marrow cells in Ldlr −/− mice did not affect lesion formation or T-cell activation. In human atherosclerotic lesions, HIF1α, STAT3, and interleukin-12 protein were found to colocalize with APCs. Conclusions— Our findings identify HIF1α to antagonize APC activation and Th1 T cell polarization during atherogenesis in Ldlr −/− mice and to attenuate the progression of atherosclerosis. These data substantiate the critical role of APCs in controlling immune mechanisms that drive atherosclerotic lesion development.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/ATVBAHA.115.306171
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2015
detail.hit.zdb_id:
1494427-3
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