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Peroxisome proliferator‐activated receptor α,γ coagonist LY465608 inhibits macrophage activation and atherosclerosis in apolipoprotein E knockout mice
Author(s) -
Zuckerman Steven H.,
Kauffman Raymond F.,
Evans Glenn F.
Publication year - 2002
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-002-0922-2
Subject(s) - apolipoprotein e , knockout mouse , endocrinology , medicine , lesion , peroxisome proliferator activated receptor , receptor , ldl receptor , macrophage , apolipoprotein b , biology , cholesterol , lipoprotein , immunology , pathology , in vitro , biochemistry , disease
The apolipoprotein F (apoF) knockout mouse has provided an approach to the investigation of the effect of both cellular and humoral processes on atherosclerotic lesion progression. In the present study, pharmacologic modulation of both interferon gamma (IFNγ)‐inducible macrophage effector functions, and atherosclerotic lesions in the apoE knockout mouse were investigated using the peroxisome proliferator‐activated receptor (PPAR) α,γ coagonist LY465608. LY465608 inhibited, in a concentration‐dependent manner, IFNγ induction of both nitric oxide synthesis and the β2 integrin CD11a in elicited peritoneal macrophages from apoE knockout mice. Similar effects were observed ex vivo following 10 d of treating mice with 10 mg/kg of LY465608. Treatment of apoE knockout mice for 18 wk with LY465608 resulted in a statistically significant 2.5‐fold reduction in atherosclerotic lesion area in en face aorta preparations. These effects were apparent in the absence of any reduction in total serum cholesterol or in lipoprotein distribution. Finally, treatment of apoE knockout mice with established atherosclerotic disease resulted in a modest but not statistically significant decrease in aortic lesional surface area. These results demonstrate the utility of PPAR coagonists in reducing the progression of the atherosclerotic lesion.