Expression of Tumor Necrosis Factor Receptor-1 in Arterial Wall Cells Promotes Atherosclerosis.
Arterioscler Thromb Vasc Biol. 2007 Mar 1; [Epub ahead of print]
Zhang L,
Peppel K,
Sivashanmugam P,
Orman ES,
Brian L,
Exum ST,
Freedman NJ.
Duke University Departments of Medicine 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.
OBJECTIVE: Mechanisms by which tumor necrosis factor (TNF)-alpha 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.
PMID: 17332495 [PubMed - as supplied by publisher]
