Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice
Andrew C. Li, … , Wulf Palinski, Christopher K. Glass
Andrew C. Li, … , Wulf Palinski, Christopher K. Glass
Published August 15, 2000
Citation Information: J Clin Invest. 2000;106(4):523-531. https://doi.org/10.1172/JCI10370.
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Article

Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice

Abstract

The peroxisome proliferator–activated receptor γ (PPARγ) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPARγ is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPARγ-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor–deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-α and gelatinase B, indicating both systemic and local actions of PPARγ. These findings suggest that PPARγ agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPARγ ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.

Authors

Andrew C. Li, Kathleen K. Brown, Mercedes J. Silvestre, Timothy M. Willson, Wulf Palinski, Christopher K. Glass

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Atherosclerosis in LDLR–/– mice fed a high-fat, cholesterol-enriched Wes...
Atherosclerosis in LDLR–/– mice fed a high-fat, cholesterol-enriched Western diet for 10 weeks. (a) Sections through the aortic root at the levels of the aortic valves were stained for elastin to highlight the medial boundaries of atherosclerotic lesions. (b) Quantitative analysis of lesion areas in control mice (C), mice treated with rosiglitazone (Ro), and mice treated with GW7845 (GW). For male mice, means ± SEM were: C, 0.161 ± 0.067 mm2/section (n = 10); Ro, 0.037 ± 0.014 mm2/section (n = 12); GW, 0.063 ± 0.027 mm2/section (n = 10). For female mice, means ± SEM were: C, 0.131 ± 0.035 mm2/section (n = 10); Ro, 0.183 ± 0.0.088 mm2/section (n = 10); GW, 0.181±0.0091 mm2/section (n = 10). NS, not statistically significant.