title: Long-term administration of 3-deazaadenosine does not alter progression of advanced atherosclerotic lesions in apolipoprotein E-deficient mice.
abstract: Inflammatory mechanisms are involved in initiation and progression of atherosclerotic lesions. Previous studies demonstrated antiinflammatory and consecutive antiatherosclerotic effects of the adenosine analogue 3-Deazaadenosine (c(3) Ado) on early lesion development. The present study evaluated the effect of long-term administration of c(3) Ado in a mouse model of advanced atherosclerosis. Apolipoprotein E-deficient mice (age, 35 weeks; n = 31) with already established advanced atherosclerotic lesions were fed either a diet supplemented with c Ado or a regular chow diet for 21 weeks. Treatment resulted in a significant reduction of serum homocysteine levels. Lesion size and lesion morphology, such as frequency of intraplaque hemorrhage, size of necrotic cores, thickness of fibrous caps, and macrophage content within the plaque, were not different between the groups. Lesion calcification, expression of alpha-actin, and intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1, were inhibited by treatment with c(3) Ado. We could not detect any effect on serum concentrations of interleukin-10 (IL-10) and interleukin-1beta (IL-1beta) or on soluble adhesion molecules intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Electromobility shift assays of protein extracts isolated from aortas did not demonstrate different binding activities of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) after treatment with c Ado. Long-term treatment with the adenosine analogue 3-Deazaadenosine did not show significant effects on progression and stability of advanced atherosclerotic lesions in older apolipoprotein E-deficient mice. A potential antiatherosclerotic effect of c(3)Ado (eg, mediated through inhibition of adhesion molecules) might therefore be limited to prevention of early lesion formation and does not seem to play a relevant role in modifying advanced atherosclerotic disease.
authors: Department of Internal Medicine III, University of Heidelberg, Germany.
authors: Michael R
authors: MR
authors: Preusch
authors: Florian
authors: F
authors: Bea
authors: Sara H
authors: SH
authors: Yang
authors: Joerg
authors: J
authors: Kreuzer
authors: Berend
authors: B
authors: Isermann
authors: Ingo
authors: I
authors: Pedal
authors: Michael E
authors: ME
authors: Rosenfeld
authors: Hugo A
authors: HA
authors: Katus
authors: Erwin
authors: E
authors: Blessing
mesh_terms: D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives*; D000818:Animals; D001013:Aorta, Thoracic; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006710:Homocysteine / Q000097:blood / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014372:Tubercidin / Q000008:administration & dosage / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D000199:Actins; D001057:Apolipoproteins E; D053583:Interleukin-1beta; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D019010:Vascular Cell Adhesion Molecule-1; C018258:3-deazaadenosine; D006710:Homocysteine; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D000241:Adenosine; D014372:Tubercidin