Effects of 3-deazaadenosine on homocysteine and atherosclerosis in apolipoprotein E-deficient mice.
OBJECTIVE
In the past decade, elevated homocysteine concentration has achieved widespread recognition as an independent risk factor in the development of atherosclerosis. 3-Deazaadenosine (c3Ado) is a potent inhibitor and substrate for S-adenosylhomocysteine hydrolase and therefore may reduce homocysteine concentrations. The current study investigated the effect of c3Ado on serum homocysteine, atherosclerotic lesions, and the expression of adhesion molecules in apoE-knockout mice.


RESULTS
Animals were placed on an atherogenic diet with or without c3Ado for 12 and 24 weeks. Frozen cross-sections of the aortic sinus and the proximal aorta were analyzed by computer-aided planimetry for fatty plaque formation. Macrophages, VCAM-1 and ICAM-1 were quantified by immunhistochemistry and oligo-cell reverse transcription polymerase chain reaction after laser microdissection. Application of c3Ado resulted in significant reduction of homocysteine levels by 35.9 and 45.3% after 12 and 24 weeks, respectively (P < 0.001). Neointimal area and atherosclerotic plaque formation were significantly reduced in animals treated with c3Ado (P < 0.01). Moreover, monocyte adhesion and concomitant ICAM-1 and VCAM-1 antigen and RNA expression on the endothelial layer were significantly reduced (P < 0.001, P < 0.01).


CONCLUSIONS
Our results demonstrate that c3Ado induces a marked reduction of homocysteine concentrations which might explain in part the anti-atherogenic effect of the drug.
Langheinrich
Alexander Claus
AC
Department of Diagnostic Radiology, Justus-Liebig Universität Giessen, Klinikstr. 36, 35385, Giessen, Germany. alexander.langheinrich@radiol.med.uni-giessen.de
Braun-Dullaeus
Ruediger Christian
RC
Walker
Gerhard
G
Jeide
Ina
I
Schilling
Ralph
R
Tammoscheit
Kai
K
Dreyer
Thomas
T
Fink
Ludger
L
Bohle
Rainer Maria
RM
Haberbosch
Werner
W
D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology*; D001483:Base Sequence; D001707:Biopsy, Needle; D002784:Cholesterol / Q000378:metabolism; D018076:DNA, Complementary / Q000032:analysis; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006710:Homocysteine / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D012850:Sinus of Valsalva / Q000187:drug effects / Q000473:pathology; D000637:Transaminases / Q000378:metabolism; D014372:Tubercidin / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D001057:Apolipoproteins E; D018076:DNA, Complementary; D012333:RNA, Messenger; D006710:Homocysteine; D002784:Cholesterol; D000637:Transaminases; D014372:Tubercidin