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

Objective : Tumor necrosis factor-α (TNFα) 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 TNFα affects atherosclerosis minimally or not under conditions that allow fatty streak formation. Here, we examined the possible role of TNFα in advanced and complex atherosclerotic lesions. Methods and results : To induce atherosclerosis, TNFα-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-Leiden Tnf−/− and control mice. Although absence of TNFα did not affect the quantitative area of atherosclerosis, APOE*3-Leiden Tnf−/− 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-Leiden Tnf−/− 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 TNFα stimulates the formation of lesions towards an advanced phenotype, with more lesion necrosis and a lower incidence of apoptosis.