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


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.
Zhang
Lisheng
L
Departments of Medicine (Cardiology), Duke University Medical Center, Durham, NC 27710, USA.
Peppel
Karsten
K
Sivashanmugam
Perumal
P
Orman
Eric S
ES
Brian
Leigh
L
Exum
Sabrina T
ST
Freedman
Neil J
NJ
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D001681:Biological Assay; D015415:Biomarkers / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D004195:Disease Models, Animal; D018450:Disease Progression; D005500:Follow-Up Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis*
D015415:Biomarkers; D047888:Receptors, Tumor Necrosis Factor, Type I