Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr–/– mice
Bin Zhao, … , Lawrence L. Rudel, Shobha Ghosh
Bin Zhao, … , Lawrence L. Rudel, Shobha Ghosh
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2983-2992. https://doi.org/10.1172/JCI30485.
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Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr–/– mice

Abstract

Accumulation of cholesteryl esters (CEs) in macrophage foam cells, central to atherosclerotic plaque formation, occurs as a result of imbalance between the cholesterol influx and efflux pathways. While the uptake, or influx, of modified lipoproteins is largely unregulated, extracellular acceptor-mediated free cholesterol (FC) efflux is rate limited by the intracellular hydrolysis of CE. We previously identified and cloned a neutral CE hydrolase (CEH) from human macrophages and demonstrated its role in cellular CE mobilization. In the present study, we examined the hypothesis that macrophage-specific overexpression of CEH in atherosclerosis-susceptible Ldlr–/– mice will result in reduction of diet-induced atherosclerosis. Transgenic mice overexpressing this CEH specifically in the macrophages (driven by scavenger receptor promoter/enhancer) were developed and crossed into the Ldlr–/– background (Ldlr–/–CEHTg mice). Macrophage-specific overexpression of CEH led to a significant reduction in the lesion area and cholesterol content of high-fat, high-cholesterol diet–induced atherosclerotic lesions. The lesions from Ldlr–/–CEHTg mice did not have increased FC, were less necrotic, and contained significantly higher numbers of viable macrophage foam cells. Higher CEH-mediated FC efflux resulted in enhanced flux of FC from macrophages to gall bladder bile and feces in vivo. These studies demonstrate that by enhancing cholesterol efflux and reverse cholesterol transport, macrophage-specific overexpression of CEH is antiatherogenic.

Authors

Bin Zhao, Jingmei Song, Woon N. Chow, Richard W. St. Clair, Lawrence L. Rudel, Shobha Ghosh

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Figure 5

Lesions in Ldlr–/–CEHTg mice are more cellular.

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Lesions in Ldlr–/–CEHTg mice are more cellular. Hearts f...
Hearts from Western diet–fed mice were fixed, paraffin embedded, and sectioned as described in Methods. (A) Representative aortic sinus lesion on 1 of the leaflets, stained with Masson’s Trichrome reagent. Original magnification, ×200. The lumen (L) of the aortic sinus is so marked for orientation. The red staining of the cytoplasm illustrates the highly cellular nature of the lesion in Ldlr–/–CEHTg mice. Limited blue staining in the core of the plaque indicates reduced collagen levels in the lesions of Ldlr–/– compared with Ldlr–/–CEHTg mice. (B) Magnification of the boxed areas in A. Serial sections were stained with H&E. Arrowheads mark the nuclei, arrows point to the cholesterol clefts, and asterisks indicate foam cells. (C) A second serial section was immunostained with antibody to macrophage marker MOMA-2. Intact foam cells (asterisks) containing intracellular lipid droplets and stained brown with MOMA-2 antibody are visible throughout the lesion from Ldlr–/–CEHTg but not in lesion from Ldlr–/– mice. Original magnification, ×600 (B and C).