Elevating high-density lipoprotein cholesterol in apolipoprotein E-deficient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content

Background-HDL cholesterol levels are inversely correlated with coronary he art disease risk in humans, and in animal studies, HDL elevation decreases formation and progression of foam-cell lesions. The potential for HDL to af fect 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 repl aced segments of the abdominal aorta of 4-month-old EKO syngeneic mice not expressing (plasma HDL cholesterol approximate to 26 mg/dL) or expressing ( HDL approximate to 64 mg/dL) a human apoAI (hAI) transgene. Both types of r ecipients had comparable non-HDL cholesterol levels. Five months after tran splantation, mice were killed and grafts analyzed. Compared with lesion are a in pretransplant mice (0.14 +/-0.04 mm(2), mean +/- SEM), there was progr ession in the EKO recipients (0.39 +/-0.06 mm(2), P <0.01). Compared with E KO recipients, hAI/EKO recipients had retarded progression (0.24 +/-0.04 mm (2), P <0.05). Immunostaining for CD68 and other macrophage-associated prot eins, monocyte chemoattractant protein-1, acyl coenzyme A:cholesterol acylt ransferase, and tissue factor, in lesions of pretransplant and EKO recipien t mice showed abundant macrophages. In contrast, compared with any other gr oup, lesional macrophage area in hAI/EKO mice decreased > 80% (P <0.003), a nd smooth muscle cell content (alpha -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 progressi on of advanced atherosclerotic lesions and remodels them to a more stable-a ppearing phenotype.