Tumor necrosis factor-α promotes atherosclerotic lesion progression in APOE*3-leiden transgenic mice

Objective: Tumor necrosis factor-alpha (TNF alpha) is a pleiotropic cytokine exerting both inflammatory and cell death modulatory activity, and is thought to play a role in the pathogenesis of atherosclerosis. Studies in mice indicated that TNFa affects atherosclerosis minimally or not under conditions that allow fatty streak fort-nation. Here, we examined the possible role of TNFa in advanced and complex atherosclerotic lesions. Methods and results: To induce atherosclerosis, TNF alpha-deficient (Tnf-/-) APOE*3-Leiden and control APOE*3-Leiden only mice were fed a cholesterol-rich diet. Comparable levels of plasma cholesterol and triglycerides and the systemic inflammatory parameters, serum amyloid A and soluble intercellular adhesion molecule-1 were found in APOE*3-LeidenTnf-/- and control mice. Although absence of TNF alpha did not affect the quantitative area of atherosclerosis, APOE*3-LeidenTnf-/- mice had a higher relative number of early lesions (46.1% vs. 21.4%) and a lower relative number of advanced lesions (53.9% vs. 78.6%, P=0.04). In addition, the advanced lesions in APOE*3-LeidenTnf-/- mice showed less necrosis (9.9 +/- 12.1% vs. 23.4 +/- 19.3% of total lesion area, P=0.04) and an increase in apoptosis (1.5 +/- 1.5% vs. 0.4 +/- 0.6% of total nuclei, P=0.03). Conclusions: Our data indicate that TNF alpha stimulates the formation of lesions towards an advanced phenotype, with more lesion necrosis and a lower incidence of apoptosis. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.