| Myeloid-specific Krüppel-like factor 2 inactivation increases macrophage and neutrophil adhesion and promotes atherosclerosis. | |
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MedLine Citation:
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PMID: 22474254 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Hemizygous deficiency of the transcription factor Krüppel-like factor 2 (KLF2) has been shown previously to augment atherosclerosis in hypercholesterolemic mice. However, the cell type responsible for the increased atherosclerosis due to KLF2 deficiency has not been identified. This study examined the consequence of myeloid cell-specific KLF2 inactivation in atherosclerosis. METHODS AND RESULTS: Cell-specific knockout mice were generated by Cre/loxP recombination. Macrophages isolated from myeloid-specific Klf2 knockout (myeKlf2(-/-)) mice were similar to myeKlf2(+/+) macrophages in response to activation, polarization, and lipid accumulation. However, in comparison to myeKlf2(+/+) macrophages, myeKlf2(-/-) macrophages adhered more robustly to endothelial cells. Neutrophils from myeKlf2(-/-) mice also adhered more robustly to endothelial cells, and fewer myeKlf2(-/-) neutrophils survived in culture over a 24-hour period in comparison with myeKlf2(+/+) neutrophils. When myeKlf2(-/-) mice were mated to Ldlr(-/-) mice and then fed a high fat and high cholesterol diet, significant increase in atherosclerosis was observed in the myeKlf2(-/-)Ldlr(-/-) mice compared with myeKlf2(+/+)Ldlr(-/-) littermates. The increased atherosclerosis in myeKlf2(-/-)Ldlr(-/-) mice was associated with elevated presence of neutrophils and macrophages, with corresponding increase of myeloperoxidase as well as chlorinated and nitrosylated tyrosine epitopes in their lesion areas compared with myeKlf2(+/+)Ldlr(-/-) mice. CONCLUSIONS: This study documents a role for myeloid KLF2 expression in modulating atherosclerosis. The increased neutrophil accumulation and atherosclerosis progression with myeloid-specific KLF2 deficiency also underscores the importance of neutrophils in promoting vascular oxidative stress and atherosclerosis. Collectively, these results suggest that elevating KLF2 expression may be a novel strategy for prevention and treatment of atherosclerosis. |
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Authors:
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Jerry B Lingrel; Robyn Pilcher-Roberts; Joshua E Basford; Palanikumar Manoharan; Jon Neumann; Eddy S Konaniah; Ramprasad Srinivasan; Vladimir Y Bogdanov; David Y Hui |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-04-03 |
Journal Detail:
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Title: Circulation research Volume: 110 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-05-14 Completed Date: 2012-07-10 Revised Date: 2013-05-13 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1294-302 Citation Subset: IM |
Affiliation:
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Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524. Jerry.Lingrel@uc.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Atherosclerosis / immunology*, pathology Cell Adhesion / immunology* Cell Death / immunology Endothelial Cells / cytology, immunology Female Hypercholesterolemia / immunology, pathology Kruppel-Like Transcription Factors / genetics*, metabolism* Lymphocyte Count Macrophages / cytology, immunology* Male Mice Mice, Inbred C57BL Mice, Knockout Neutrophils / cytology, immunology* Vasculitis / immunology, pathology |
| Grant Support | |
ID/Acronym/Agency:
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DK74932/DK/NIDDK NIH HHS; HL78806/HL/NHLBI NIH HHS; R01 DK074932/DK/NIDDK NIH HHS; R01 HL078806/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Klf2 protein, mouse; 0/Kruppel-Like Transcription Factors |
| Comments/Corrections | |
Comment In:
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Circ Res. 2012 May 11;110(10):1266
[PMID:
22581916
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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