Abstract 121: Inhibition of OX40 Ligand Suppresses the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice
Background: Atherosclerotic lesions are characterized by infiltration of inflammatory cells (e.g. macrophages and T-lymphocytes), for which immunological mechanism(s) may be involved. Both soluble and contact-dependent mediators from T-cells may be crucial in the development of atherosclerosis. Among them, OX40, a membrane-bound molecule of the tumor-necrosis-factor-receptor superfamily, is expressed in activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we examined whether the vascular OX40/OX40L system is involved in the pathogenesis of atherosclerosis.
Method and Results: We first demonstrated by immunostaining that OX40L was strongly expressed in endothelium of atherosclerotic human coronary arteries (n=5). We then examined whether or not the OX40/OX40L system influences the development of atherosclerosis in apolipoprotein E-deficient (ApoE−/−) mice of both genders at 10 weeks of age. They were maintained on a high-fat diet and treated with either MGP34 antibody (specific OX40L blocking antibody, 20 mg/kg IP, twice a week, n=7) or a control antibody (Rat IgG, 20 mg/kg IP, twice a week, n=8) for 10 weeks. After the long-term antibody treatment, lipid-deposition area in aortic atheroma (measured by oil-red O staining) was significantly smaller in female ApoE−/− mice treated with MGP34 antibody than in those treated with a control antibody (0.63 ±− 0.14 mm2 vs. 0.93 ±−0.12 mm2, P<0.05, n=7). However, this was not the case in male ApoE−/− mice (n=8). Next, we examined whether OX40/OX40L originated from bone marrow (BM)-derived cells also contribute to the development of atherosclerosis. ApoE−/− mice were lethally irradiated and transplanted with BM cells from either wild-type (WT) or OX40L-KO mice (n=9 each). After 12 weeks of high-fat diet, the extent of aortic atheroma was comparable between the 2 groups (WT vs. KO, 14.5 ±− 7.5% vs. 17.4 ±− 4.7%).
Conclusions: These results suggest that the OX40/OX40L system in blood vessels, but not that in BM, is substantially involved in the development of atherosclerosis and that there seems to be a gender difference in the contribution of this system to the pathogenesis of atherosclerosis.