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Updated: Sep 30, 2026
Induction of Atherosclerotic Plaques Through Activation of Mineralocorticoid Receptors in Apolipoprotein E-deficient Mice
Published on: September 26, 2018
Peroxisome proliferator-activated receptor alpha,gamma coagonist LY465608 inhibits macrophage activation and
Steven H Zuckerman1, Raymond F Kauffman, Glenn F Evans
1Division of Cardiovascular Research, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA. Zuckerman_Steven@Lilly.com
Abstract:
The apolipoprotein E (apoE) 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 (IFNgamma)-inducible macrophage effector functions, and atherosclerotic lesions in the apoE knockout mouse were investigated using the peroxisome proliferator-activated receptor (PPAR) alpha,gamma coagonist LY465608. LY465608 inhibited, in a concentration-dependent manner, IFNgamma induction of both nitric oxide synthesis and the beta 2 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 apoF 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.
Insights
Peroxisome proliferator-activated receptor (PPAR) coagonists like LY465608 significantly reduce atherosclerotic lesion progression in apoE knockout mice. This occurs by modulating macrophage functions without altering cholesterol levels.
Area of Science:
- Cardiovascular Research
- Immunology
- Pharmacology
Background:
- Apolipoprotein E (apoE) knockout mice are crucial models for studying atherosclerosis.
- Interferon gamma (IFNγ) influences macrophage functions involved in lesion development.
Purpose of the Study:
- To investigate the effects of the PPAR alpha,gamma coagonist LY465608 on IFNγ-inducible macrophage functions and atherosclerotic lesions in apoE knockout mice.
Main Methods:
- LY465608 was used to modulate macrophage effector functions in vitro and in vivo.
- ApoE knockout mice were treated with LY465608 for 18 weeks.
- Atherosclerotic lesion area was quantified in en face aorta preparations.
Main Results:
- LY465608 inhibited IFNγ-induced nitric oxide synthesis and CD11a expression in macrophages.
- Treatment led to a significant 2.5-fold reduction in atherosclerotic lesion area.
- These benefits occurred without changes in total serum cholesterol or lipoprotein distribution.
Conclusions:
- PPAR coagonists are effective in reducing atherosclerotic lesion progression.
- LY465608 demonstrates therapeutic potential for atherosclerosis by targeting macrophage pathways.