3-deazaadenosine prevents adhesion molecule expression and atherosclerotic lesion formation in the aortas of C57BL/6J mice.
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.
Walker
G
G
Department of Cardiology, Giessen University, Germany.
Langheinrich
A C
AC
Dennhauser
E
E
Bohle
R M
RM
Dreyer
T
T
Kreuzer
J
J
Tillmanns
H
H
Braun-Dullaeus
R C
RC
Haberbosch
W
W
D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005260:Female; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000096:biosynthesis*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D014372:Tubercidin / Q000494:pharmacology*; D017539:Tunica Intima / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000096:biosynthesis
D019010:Vascular Cell Adhesion Molecule-1; C018258:3-deazaadenosine; D018799:Intercellular Adhesion Molecule-1; D014372:Tubercidin