Background We previously showed that the progression of atherosclerosis in the Reversa mouse (Ldlr−/−Apob100/100Mttpfl/flMx1Cre+/+) was arrested when the hyperlipidemia was normalized by inactivating the gene for microsomal triglyceride transfer protein. Here we tested whether atherosclerosis would regress if the lipid levels were reduced after advanced plaques formed. Methods and Results Reversa mice were fed an atherogenic diet for 16 weeks. Plasma lipid levels were then reduced. Within 2 weeks, this reduction led to decreased monocyte-derived (CD68+) cells in atherosclerotic plaques and was associated with emigration of these cells out of plaques. Also, the fall in lipid levels was accompanied by lower plaque lipid content and by reduced expression in plaque CD68+ cells of inflammatory genes and higher expression of genes for markers of anti-inflammatory M2 macrophages. Plaque composition was affected more than plaque size, with the decreased content of lipid and CD68+ cells balanced by a higher content of collagen. When a reduced lipid levels was combined with the administration of pioglitazone to simulate the clinical aggressive lipid management and PPARγ agonist treatment, the rate of depletion of plaque CD68+ cells was unaffected, but there was a further increase in their expression of anti-inflammatory macrophage markers. Conclusion The Reversa mouse model is a new model of atherosclerosis regression. After lipid lowering favorable changes in plaque composition were independent of changes in size. In addition, plaque CD68+ cells became less inflammatory, an effect enhanced by treatment with pioglitazone.

OBJECTIVEPatients with diabetes have increased cardiovascular risk. Atherosclerosis in these patients is often associated with increased plaque macrophages and dyslipidemia. We hypothesized that diabetic atherosclerosis involves processes that impair favorable effects of lipid reduction on plaque macrophages.RESEARCH DESIGN AND METHODSReversa mice are LDL receptor–deficient mice that develop atherosclerosis. Their elevated plasma LDL levels are lowered after conditional knockout of the gene encoding microsomal triglyceride transfer protein. We examined the morphologic and molecular changes in atherosclerotic plaques in control and streptozotocin-induced diabetic Reversa mice after LDL lowering. Bone marrow–derived macrophages were also used to study changes mediated by hyperglycemia.RESULTSReversa mice were fed a western diet for 16 weeks to develop plaques (baseline). Four weeks after lipid normalization, control (nondiabetic) mice had reduced plasma cholesterol (−77%), plaque cholesterol (−53%), and plaque cells positive for macrophage marker CD68+ (−73%), but increased plaque collagen (+116%) compared with baseline mice. Diabetic mice had similarly reduced plasma cholesterol, but collagen content increased by only 34% compared with baseline; compared with control mice, there were lower reductions in plaque cholesterol (−30%) and CD68+ cells (−41%). Diabetic (vs. control) plaque CD68+ cells also exhibited more oxidant stress and inflammatory gene expression and less polarization toward the anti-inflammatory M2 macrophage state. Many of the findings in vivo were recapitulated by hyperglycemia in mouse bone marrow–derived macrophages.CONCLUSIONSDiabetes hindered plaque regression in atherosclerotic mice (based on CD68+ plaque content) and favorable changes in plaque macrophage characteristics after the reduction of elevated plasma LDL.