The effect of the long term aspirin administration on the progress of atherosclerosis in apoE-/- LDLR-/- double knockout mouse.

UNLABELLED

We have investigated the effects of differential aspirin doses on atherogenesis. Aspirin was given to homozygous, apoE(-/-) and LDLR(-/-) double deficient mice for 12 weeks. The development of arteriosclerosis was determined morphologically by image analysis and endothelial cell function was assessed by measurement of peripheral nitric oxide (NO).

METHODS

ApoE(-/-) LDLR(-/-)double knockout mice were bred and maintained with a high fat diet containing aspirin (4 and 40 mg/kg B.W. /day) for twelve weeks. The development of arteriosclerosis was monitored by estimating the total area of atherosclerotic lesions in the entire aorta. Acetylcholine-induced NO release was measured in vivo using electrochemical sensors. The expression of eNOS on the endothelial surface was determined by immuno-staining. Plasma prostaglandin F1alpha (PGF(1 alpha)), serum thromboxian B(2) (TXB(2)) and total cholesterol were measured using enzymatic assay. Bleeding time was measured by tail cut method.

RESULTS

Arteriosclerosis in the 4 mg/kg/day aspirin group was decreased significantly compared with the placebo group, but not in the 40 mg/kg/day aspirin group. Acetylcholine-induced NO release was significantly depressed in the 40 mg/kg/day aspirin group. Immunochemical analysis with anti-eNOS antibody supported these findings. In the 4 mg/kg/day aspirin group, the severe suppression of PGI(2) production was not confirmed in spite of decreasing TXB(2) production, but not in the 40 mg/kg/day aspirin group.

CONCLUSION

Our results suggest that endothelial dysfunction with low dose aspirin improved, reduced progression of atherosclerosis in apoE(-/-) and LDLR(-/-) double deficient mice and provides a pathophysiological basis for the beneficial effects of aspirin in atherosclerosis, and low doses appeared to be more efficient than high doses.