Elevating High-Density Lipoprotein Cholesterol in Apolipoprotein E-Deficient Mice Remodels Advanced Atherosclerotic Lesions by Decreasing Macrophage and Increasing Smooth Muscle Cell Content

• DOI: 10.1161/hc4501.098952
• Publication Date: 2007-09-28T18:31:09Z
• Authors: James X. Rong; Jie Li; Ernane D. Reis; Robin P. Choudhury; Hayes M. Dansky; Valerie I. Elmalem; John T. Fallon; Jan L. Breslow; Edward A. Fisher
• Keywords: Mice, Knockout; Apolipoprotein A-I; Arteriosclerosis; Macrophages; Cholesterol, HDL; Mice, Transgenic; Actins; Muscle, Smooth, Vascular; 3. Good health; Mice; 03 medical and health sciences; Apolipoproteins E; Cholesterol; 0302 clinical medicine; Animals; Humans; Aorta

Background

HDL cholesterol levels are inversely correlated with coronary heart disease risk in humans, and in animal studies, HDL elevation decreases formation and progression of foam-cell lesions. The potential for HDL to affect preexisting advanced atherosclerotic lesions is not known. To approach this issue, we used a novel mouse aortic transplantation model.

Methods and Results

ApoE-deficient (EKO) mice were fed a Western-type diet for 6 months, and thoracic aortic segments containing advanced lesions replaced segments of the abdominal aorta of 4-month-old EKO syngeneic mice not expressing (plasma HDL cholesterol ≈26 mg/dL) or expressing (HDL ≈64 mg/dL) a human apoAI (hAI) transgene. Both types of recipients had comparable non-HDL cholesterol levels. Five months after transplantation, mice were killed and grafts analyzed. Compared with lesion area in pretransplant mice (0.14±0.04 mm 2 , mean±SEM), there was progression in the EKO recipients (0.39±0.06 mm 2 , P <0.01). Compared with EKO recipients, hAI/EKO recipients had retarded progression (0.24±0.04 mm 2 , P <0.05). Immunostaining for CD68 and other macrophage-associated proteins, monocyte chemoattractant protein-1, acyl coenzyme A:cholesterol acyltransferase, and tissue factor, in lesions of pretransplant and EKO recipient mice showed abundant macrophages. In contrast, compared with any other group, lesional macrophage area in hAI/EKO mice decreased >80% ( P <0.003), and smooth muscle cell content (α-actin staining) increased >300% ( P <0.006). The decrease in macrophages and increase in smooth muscle cells was primarily in the superficial subendothelial layer.

Conclusions

Increasing HDL cholesterol levels in EKO mice retards progression of advanced atherosclerotic lesions and remodels them to a more stable-appearing phenotype.