Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) play an important role during the development of atherosclerosis. 3-Deazaadenosine (c(3)Ado), an adenosine analogue, inhibits endothelial-leukocyte adhesion and ICAM-1-expression in vitro. We hypothesized that c(3)Ado is able to prevent the expression of adhesion molecules and atherosclerotic lesion formation in female C57BL/6J mice. The animals were placed on an atherogenic diet with or without c(3)Ado for 9 weeks. Frozen cross sections of the proximal ascending aorta just beyond the aortic sinus were stained with oil red O, hematoxylin, and elastic van Gieson's stains and were analyzed by computer-aided planimetry for fatty plaque formation and neointimal proliferation. Monoclonal antibodies against CD11b (macrophages), VCAM-1, and ICAM-1 were used for immunohistochemistry. Mice on the atherogenic diet demonstrated multiple (5.4+/-1.6 per animal) lesions covering 3.4+/-2.8% of the endothelium and a marked neointima when compared with control mice (4501+/-775 versus 160+/-38 microm(2), P<0.001). Mice on the cholesterol-rich diet without c(3)Ado showed strong endothelial coexpression of ICAM-1 and VCAM-1. Moreover, there was a 10-fold increase in monocyte accumulation on the endothelial surface (33. 3+/-4.9 versus 3.8+/-1.2, P<0.004). In contrast, in mice treated with c(3)Ado, expression of ICAM-1 and VCAM-1 as well as monocyte adhesion and infiltration were almost completely inhibited. Furthermore, these mice did not show any fatty streak formation or neointima formation (125+/-32 microm(2)). Our results demonstrate that c(3)Ado can inhibit diet-induced fatty streak formation and the expression of endothelial ICAM-1 and VCAM-1 in C57BL/6J mice. This may provide a novel pharmacological approach in the prevention and treatment of atherosclerosis.