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Interleukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet in a murine apolipoprotein E heterozygote model: pharmacotherapeutic implications.
- Source :
-
Circulation [Circulation] 2004 Sep 21; Vol. 110 (12), pp. 1678-85. Date of Electronic Publication: 2004 Sep 07. - Publication Year :
- 2004
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Abstract
- Background: Current data demonstrate that progressive atherosclerosis is associated with activation of the inflammatory process, as evidenced by systemic elevations of molecules such as tumor necrosis factor, interleukin (IL)-6, and IL-1. It has been postulated that inflammatory events within an atherogenic lesion are induced by oxidized LDL. Recent evidence suggests that infectious agents, including those that cause periodontal disease, may also play an important role. Studies presented here tested the hypothesis that IL-1 receptor (IL-1R1) signaling plays a crucial role in bacteria- and/or high-fat diet (HFD)-enhanced atherogenesis.<br />Methods and Results: Ten-week-old ApoE+/- mice lacking either 1 IL-1R1 allele (ApoE+/-/IL-1R1+/-) or 2 IL-1R1 alleles (ApoE+/-/IL-1R1-/-) fed either an HFD or regular chow were inoculated intravenously with live Porphyromonas gingivalis (P gingivalis) (10(7) CFU), an important periodontal pathogen, or vehicle once per week for 14 or 24 consecutive weeks. Histomorphometry of plaque cross-sectional area in the proximal aortas, en face measurement of plaque area over the aortic trees, and ELISA for systemic proinflammatory mediators were performed. Atherosclerotic lesions of proximal aortas and aortic tree were substantially reduced in ApoE+/-/IL-1R1-/- mice than in ApoE+/-/IL-1R1+/- mice challenged with P gingivalis. At 24 weeks after P gingivalis inoculation, proximal aortic lesion size quantified by histomorphometry was 5-fold-reduced in chow-fed ApoE+/-/IL-1R1-/- mice than in ApoE+/-/IL-1R1+/- mice (P<0.05). In the HFD group, ApoE+/-/IL-1R1-/- mice exhibited marked attenuation of the progression of atherosclerotic lesions (78% to 97%), with and without P gingivalis inoculation (P<0.05).<br />Conclusions: Ablation of IL-1R1 under P gingivalis challenge and/or an HFD reduced the progression of atherosclerotic plaques. These results indicate that IL-1 plays a crucial role in bacteria- and/or HFD-enhanced atherogenesis.
- Subjects :
- Animals
Aortic Diseases etiology
Aortic Diseases metabolism
Aortic Diseases pathology
Apolipoproteins E deficiency
Apolipoproteins E genetics
Arteriosclerosis metabolism
Arteriosclerosis pathology
Bacteroidaceae Infections microbiology
Diet, Atherogenic
Female
Genotype
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Porphyromonas gingivalis pathogenicity
Random Allocation
Receptors, Interleukin-1 deficiency
Receptors, Interleukin-1 genetics
Serum Amyloid A Protein analysis
Arteriosclerosis etiology
Bacteroidaceae Infections complications
Dietary Fats toxicity
Interleukin-1 physiology
Receptors, Interleukin-1 physiology
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 110
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 15353494
- Full Text :
- https://doi.org/10.1161/01.CIR.0000142085.39015.31