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

Yamamoto, Y.; Yamashita, T.; Kitagawa, F.; Sakamoto, K.; Giddings, J.C.; Yamamoto, J.

doi:10.1016/j.thromres.2009.11.008

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Volume 125, Issue 3 , Pages 246-252, March 2010

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

Y. Yamamoto
- Laboratory of Physiology, Faculty of Nutrition, and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe, Japan
T. Yamashita
- Laboratory of Physiology, Faculty of Nutrition, and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe, Japan
- Corresponding author. Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, 518, Arise, Igawadani-Cho, Nishiku, Kobe, Japan 651-2180. Tel.: +81 78 974 1551; fax: +81 78 974 5689.
F. Kitagawa
- Laboratory of Physiology, Faculty of Nutrition, and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe, Japan
K. Sakamoto
- Laboratory of Physiology, Faculty of Nutrition, and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe, Japan
J.C. Giddings
- Department of Haematology, Wales College of Medicine, Cardiff University, Cardiff, UK
J. Yamamoto
- Laboratory of Physiology, Faculty of Nutrition, and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe, Japan

Received 26 March 2009; received in revised form 14 October 2009; accepted 9 November 2009.

Abstract

We have investigated the effects of differential aspirin doses on atherogenesis. Aspirin was given to homozygous, apoE^-/- and LDLR^-/- double deficient mice for 12weeks. 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 40mg/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 F1α (PGF_1α), serum thromboxian B₂ (TXB₂) and total cholesterol were measured using enzymatic assay. Bleeding time was measured by tail cut method.

Results

Arteriosclerosis in the 4mg/kg/day aspirin group was decreased significantly compared with the placebo group, but not in the 40mg/kg/day aspirin group. Acetylcholine-induced NO release was significantly depressed in the 40mg/kg/day aspirin group. Immunochemical analysis with anti-eNOS antibody supported these findings. In the 4mg/kg/day aspirin group, the severe suppression of PGI₂ production was not confirmed in spite of decreasing TXB₂ production, but not in the 40mg/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.

Keywords: Aspirin, Atherosclerosis, Nitric oxide, Endothelial function