Abstract 1733: Tumor Necrosis Factor Receptor-1 Aggravates Aging-Associated Atherosclerosis
Aging is believed to contribute to atherogenesis independently of traditional atherosclerosis risk factors, but the mechanisms responsible for this contribution remain obscure. Although serum tumor necrosis factor (TNF) levels increase with aging, vascular cell TNF receptor-1 (TNFR1) expression does not diminish. For these reasons, we tested the hypothesis that TNFR1 contributes to aging-associated atherosclerosis. To isolate aging of the vascular wall from the effects of prolonged exposure to systemic atherogenic factors, we used carotid arteries from 18-month-old (aged) and 8-wk-old (young), congenic tnfr1−/− and WT mice as carotid interposition grafts in congenic 8-wk-old apoe−/− mice. Two weeks post-op, WT carotids developed macrophage-rich neointimal lesions. Area dimensions (mm2) of aged and young specimens, respectively, were: neointima, 0.020 ± 0.009 and 0.010 ± 0.006 (p < 0.02); media, 0.06 ± 0.02 and 0.03 ± 0.01 (p < 0.01); external diameter, 0.45 ± 0.05 and 0.39 ± 0.06 (p < 0.03). Thus, aged arteries showed greater atherosclerosis than young arteries, even at early stages of atherogenesis. ICAM-1 and MCP-1 expression, and macrophage prevalence in aged specimens were 1.9 ± 0.4-fold, 1.9 ± 0.2- and 2.5 ± 0.5-fold more (p < 0.04), respectively, than in young specimens, assessed by quantitative immunofluorescence. Seven wks post-op, neointimal area, macrophage and apoptotic (cleaved caspase-3+) cell prevalence, and MMP-9 expression were greater in aged than in young arteries, by 1.6 ± 0.3-, 2.3 ± 0.3-, 2.1 ± 0.7-, and 1.5 ± 0.2-fold (p < 0.04), while neointimal SMC prevalence and collagen content were 2.0 ± 0.2- and 1.7 ± 0.1-fold less (p < 0.04). In contrast, 7-wk-old aged and young tnfr1−/−carotid grafts had equivalent intimal and medial areas, macrophage and apoptotic (cleaved caspase-3+) cell prevalence, VCAM-1 expression, and collagen content. Neointimal and medial areas were less in tnfr1−/− than in WT arteries, by 2.7 ± 0.5-fold and 1.4 ± 0.1-fold, respectively (p < 0.05). We conclude that arterial wall aging contributes to atherosclerosis through mechanisms related to macrophage recruitment, independently of systemic factors, and that TNFR1 signaling in the arterial wall promotes aging-dependent atherosclerosis.