Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation-specific epitopes, and atherogenesis in hypercholesterolemic mice.
The effects of chronic treatment with nitric oxide-containing aspirin (NO-aspirin, NCX-4016) in comparison with regular aspirin or placebo on the development of a chronic disease such as atherosclerosis were investigated in hypercholesterolemic low-density lipoprotein (LDL)-receptor-deficient mice. Male mice were assigned randomly to receive in a volume of 10 ml/kg either placebo (n = 10), 30 mg/kg/day NO-aspirin (n = 10), or 18 mg/kg/day of regular aspirin (n = 10). After 12 weeks of treatment, the computer-assisted imaging analysis revealed that NO-aspirin reduced the aortic cumulative lesion area by 39.8 +/- 12.3% compared with that of the placebo (P < 0.001). Regular aspirin did not reduce significantly aortic lesions (-5.1 +/- 2.3%) compared with the placebo [P = 0.867, not significant (NS)]. Furthermore, NO-aspirin reduced significantly plasma LDL oxidation compared with aspirin and placebo, as shown by the significant reduction of malondialdehyde content (P < 0.001) as well as by the prolongation of lag-time (P < 0.01). Similarly, systemic oxidative stress, measured by plasma isoprostanes, was significantly reduced by treatment with NCX-4016 (P < 0.05). More importantly, mice treated with NO-aspirin revealed by immunohistochemical analysis of aortic serial sections a significant decrease in the intimal presence of oxidation-specific epitopes of oxLDL (E06 monoclonal antibody, P < 0.01), and macrophages-derived foam cells (F4/80 monoclonal antibody, P < 0.05), compared with placebo or aspirin. These data indicate that enhanced NO release by chronic treatment with the NO-containing aspirin has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic mice.
Napoli
Claudio
C
Department of Medicine, School of Medicine, Federico II University of Naples, 80131 Naples, Italy. cnapoli@ucsd.edu
Ackah
Eric
E
De Nigris
Filomena
F
Del Soldato
Piero
P
D'Armiento
Francesco P
FP
Crimi
Ettore
E
Condorelli
Mario
M
Sessa
William C
WC
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D001241:Aspirin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects / Q000473:pathology; D006937:Hypercholesterolemia / Q000150:complications* / Q000188:drug therapy*; D008077:Lipoproteins, LDL / Q000097:blood* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
D008077:Lipoproteins, LDL; D020030:Nitric Oxide Donors; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; C102148:nitroaspirin; D001241:Aspirin