Effects of 3-deazaadenosine on homocysteine and atherosclerosis in apolipoprotein E-deficient mice

Abstract

Objective: In the past decade, elevated homocysteine concentration has achieved widespread recognition as an independent risk factor in the development of atherosclerosis. 3-Deazaadenosine (c 3Ado) is a potent inhibitor and substrate for S-adenosylhomocysteine hydrolase and therefore may reduce homocysteine concentrations. The current study investigated the effect of c 3Ado on serum homocysteine, atherosclerotic lesions, and the expression of adhesion molecules in apoE-knockout mice. Methods and results: Animals were placed on an atherogenic diet with or without c 3Ado 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 c 3Ado 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 c 3Ado ( 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). Conclusion: Our results demonstrate that c 3Ado induces a marked reduction of homocysteine concentrations which might explain in part the anti-atherogenic effect of the drug.