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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1087.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Expression of Tumor Necrosis Factor Receptor-1 in Arterial Wall Cells Promotes Atherosclerosis

Lisheng Zhang; Karsten Peppel; Perumal Sivashanmugam; Eric S. Orman; Leigh Brian; Sabrina T. Exum; Neil J. Freedman

From Duke University Departments of Medicine (Cardiology) and Cell Biology, Duke University Medical Center, Durham, NC. Current address for K.P.: Jefferson University Center for Translational Medicine, 1025 Walnut St, Philadelphia, PA 19107.

Correspondence to Neil J. Freedman or Karsten Peppel, Box 3187, Duke University Medical Center, Durham, NC 27710. E-mail neil.freedman{at}duke.edu or karsten.peppel@jefferson.edu

Objective— Mechanisms by which tumor necrosis factor- (TNF) contributes to atherosclerosis remain largely obscure. We therefore sought to determine the role of the arterial wall TNF receptor-1 (TNFR1) in atherogenesis.

Methods and Results— Carotid artery-to-carotid artery interposition grafting was performed with tnfr1^–/– and congenic (C57Bl/6) wild-type (WT) mice as graft donors, and congenic chow-fed apolipoprotein E-deficient mice as recipients. Advanced atherosclerotic graft lesions developed within 8 weeks, and had 2-fold greater area in WT than in tnfr1^–/– grafts. While the prevalence of specific atheroma cells was equivalent in WT and tnfr1^–/– grafts, the overall abundance of cells was substantially greater in WT grafts. WT grafts demonstrated greater MCP-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 expression at both early and late time points, and proliferating cell nuclear antigen expression at early time points. Aortic atherosclerosis was also reduced in 14-month-old apoe^–/–/tnfr1^–/– mice, as compared with cognate apoe^–/– mice. In coculture with activated macrophages, smooth muscle cells expressing the TNFR1 demonstrated enhanced migration and reduced scavenger receptor activity.

Conclusions— TNFR1 signaling, just in arterial wall cells, contributes to the pathogenesis of atherosclerosis by enhancing arterial wall chemokine and adhesion molecule expression, as well as by augmenting medial smooth muscle cell proliferation and migration.

In carotid arterial grafts implanted into apolipoprotein E-deficient mice, TNF receptor-1 deficiency reduced atherosclerotic lesion size by 2-fold. This reduction in atherosclerosis correlated with reduced arterial wall expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and MCP-1, and reduced medial SMC proliferation. TNFR1 deficiency also reduced SMC migration toward activated macrophages.

Key Words: atherosclerosis • inflammation • mouse models • smooth muscle cells • tumor necrosis factor

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