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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2673.)
© 1999 American Heart Association, Inc.

Vascular Biology

3-Deazaadenosine Prevents Adhesion Molecule Expression and Atherosclerotic Lesion Formation in the Aortas of C57BL/6J Mice

Gerhard Walker; Alexander C. Langheinrich; Elisabeth Dennhauser; Rainer M. Bohle; Thomas Dreyer; Jörg Kreuzer; Harald Tillmanns; Ruediger C. Braun-Dullaeus; Werner Haberbosch
Abstract—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 (c³Ado), an adenosine analogue, inhibits endothelial-leukocyte adhesion and ICAM-1-expression in vitro. We hypothesized that c³Ado 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 c³Ado 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 µm², P<0.001). Mice on the cholesterol-rich diet without c³Ado 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 c³Ado, 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 µm²). Our results demonstrate that c³Ado 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.

Key Words: adenosine analogues • atherosclerosis • cell adhesion molecules • hypercholesterolemia • immunohistochemistry

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