G. Walker et al., 3-deazaadenosine prevents adhesion molecule expression and atheroscleroticlesion formation in the aortas of C57BL/6J mice, ART THROM V, 19(11), 1999, pp. 2673-2679
Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and i
ntercellular adhesion molecule-1 (ICAM-1) play an important role during the
development of atherosclerosis. 3-Deazaadenosine (c(3)Ado), an adenosine a
nalogue, inhibits endothelial-leukocyte adhesion and ICAM-1-expression in v
itro. We hypothesized that c(3)Ado is able to prevent the expression of adh
esion molecules and atherosclerotic lesion formation in female C57BL/6J mic
e. The animals were placed on an atherogenic diet with or without c(3)Ado f
or 9 weeks. Frozen cross sections of the proximal ascending aorta just beyo
nd the aortic sinus were stained with oil red O, hematoxylin, and elastic v
an Gieson's stains and were analyzed by computer-aided planimetry for fatty
plaque formation and neointimal proliferation. Monoclonal antibodies again
st CD11b (macrophages), VCAM-1, and ICAM-1 were used for immunohistochemist
ry. Mice on the atherogenic diet demonstrated multiple (5.4 +/- 1.6 per ani
mal) lesions covering 3.4 +/- 2.8% of the endothelium and a marked neointim
a when compared with control mice (4501 +/- 775 versus 160 +/- 38 mu m(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-fo
ld 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)Ad
o, expression of ICAM-1 and VCAM-1 as well as monocyte adhesion and infiltr
ation were almost completely inhibited. Furthermore, these mice did not sho
w any fatty streak formation or neointima formation (125 +/- 32 mu m(2)). O
ur results demonstrate that c(3)Ado can inhibit diet-induced fatty streak f
ormation and the expression of endothelial ICAM-1 and VCAM-1 in C57BL/6J mi
ce. This may provide a novel pharmacological approach in the prevention and
treatment of atherosclerosis.