NO-donating aspirin and aspirin partially inhibit age-related atherosclerosis but not radiation-induced atherosclerosis in ApoE null mice.
BACKGROUND
We previously showed that irradiation to the carotid arteries of ApoE(-/-) mice accelerated the development of macrophage-rich, inflammatory atherosclerotic lesions, prone to intra-plaque hemorrhage. In this study we investigated the potential of anti-inflammatory and anti-coagulant intervention strategies to inhibit age-related and radiation-induced atherosclerosis.


RESULTS
ApoE(-/-) mice were given 0 or 14 Gy to the neck and the carotid arteries and aortic arches were harvested at 4 or 30 weeks after irradiation. Nitric oxide releasing aspirin (NCX 4016, 60 mg/kg/day) or aspirin (ASA, 30 or 300 mg/kg/day) were given continuously in the chow. High dose ASA effectively blocked platelet aggregation, while the low dose ASA or NCX 4016 had no significant effect on platelet aggregation. High dose ASA, but not NCX 4016, inhibited endothelial cell expression of VCAM-1 and thrombomodulin in the carotid arteries at 4 weeks after irradiation; eNOS and ICAM-1 levels were unchanged. After 30 weeks of follow-up, NCX 4016 significantly reduced the total number of lesions and the number of initial macrophage-rich lesions in the carotid arteries of unirradiated mice, but these effects were not seen in the brachiocephalic artery of the aortic arch (BCA). In contrast, high dose ASA lead to a decrease in the number of initial lesions in the BCA, but not in the carotid artery. Both high dose ASA and NCX 4016 reduced the collagen content of advanced lesions and increased the total plaque burden in the BCA of unirradiated mice. At 30 weeks after irradiation, neither NCX 4016 nor ASA significantly influenced the number or distribution of lesions, but high dose ASA lead to formation of collagen-rich "stable" advanced lesions in carotid arteries. The total plaque area of the irradiated BCA was increased after ASA, but the plaque burden was very low compared with the carotid artery.


CONCLUSIONS
The development and characteristics of radiation-induced atherosclerosis varied between different arteries but could not be circumvented by anti-inflammatory and anti-coagulant therapies. This implicates other underlying mechanistic pathways compared to age-related atherosclerosis.
Hoving
Saske
S
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Heeneman
Sylvia
S
Gijbels
Marion J J
MJ
te Poele
Johannes A M
JA
Bolla
Manlio
M
Pol
Jeffrey F C
JF
Simons
Michelle Y
MY
Russell
Nicola S
NS
Daemen
Mat J
MJ
Stewart
Fiona A
FA
D000367:Age Factors; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001241:Aspirin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000276:immunology; D002339:Carotid Arteries / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation / Q000187:drug effects / Q000528:radiation effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D014965:X-Rays / Q000009:adverse effects*
D001057:Apolipoproteins E; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C102148:nitroaspirin; D001241:Aspirin