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(Circulation. 2004;110:1678-1685.)
© 2004 American Heart Association, Inc.

Vascular Medicine

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

Hunghui Chi, DDS; Emmanuel Messas, MD, MSc; Robert A. Levine, MD; Dana T. Graves, DDS, DSc; Salomon Amar, DDS, PhD

From the Department of Periodontology and Oral Biology (H.C., D.T.G., S.A.), School of Dental Medicine, Department of Pathology, Boston University, and Massachusetts General Hospital (E.M., R.A.L.), Boston, Mass.

Correspondence to Salomon Amar, DDS, PhD, Department of Periodontology and Oral Biology, Boston University, 700 Albany St, W201E, Boston, MA 02118. E-mail samar{at}bu.edu

Received December 29, 2003; de novo received March 30, 2004; revision received May 4, 2004; accepted May 6, 2004.

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.

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) (10⁷ 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)

Conclusion— 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.

Key Words: atherosclerosis • infection • interleukins • cardiovascular diseases • Porphyromonas gingivalis

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