Reversal of Hyperlipidemia With a Genetic Switch Favorably Affects the Content and Inflammatory State of Macrophages in Atherosclerotic Plaques

Abstract

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.

Comparison of Contrast Agents for Atherosclerosis Imaging Using Cultured Macrophages: FDG Versus Ultrasmall Superparamagnetic Iron Oxide

“…4), suggesting the difficulty of visualizing only M2 macrophages in distinction from nonpolarized macrophages by USPIO. Recently, it has been reported that the status of macrophage polarization in atherosclerotic plaques was dramatically changed in the progression and regression process of atherosclerosis using an experimental murine model (8,25). In addition, a substantial number of macrophages were polarized in those lesions.…”

“…These results suggest that 18 F-FDG PET should dominantly visualize the M1 macrophage-infiltrated area. Some reports have suggested that 18 F-FDG PET may be useful to monitor the therapeutic effects of drugs (33)(34)(35), and some of the drugs are reported to affect the polarization of macrophages (8,36). Because therapies that reduce M1 macrophages are garnering more attention, it becomes increasingly important to select appropriate imaging methods that accurately detect plaque development.…”

“…Furthermore, MR imaging with ultrasmall superparamagnetic iron oxide particles (USPIO)-which are also efficiently taken up by macrophages in the atherosclerotic lesion (5,6)-is used to quantify atherosclerotic plaques (6). Recently, macrophages have been considered as heterogeneous cells, which can be differently polarized in atherosclerotic plaques (7)(8)(9). Classically activated M1 macrophages promote the destabilization of atherosclerotic plaques, whereas alternatively activated M2 macrophages stimulate reparative processes, leading to stabilization of atherosclerotic plaques (10).…”

Macrophages of genetically characterized familial hypercholesterolaemia patients show up‐regulation of LDL‐receptor‐related proteins

“…Macrophages CD16 + are usually related to a mature M2‐phenotype, also characterized for being positive for CD163 20 a scavenger receptor of the haemoglobin–haptoglobin complex involved in haeme catabolism through a process mediated by regulation of the haeme oxygenase‐1 (HMOX1) expression 79. The presence of CD163 macrophages in human atherosclerotic lesions has been also associated with anti‐inflammatory properties mediated through IL10 21, and studies in mice ApoE −/− models have associated plaque regression with the presence of M2 macrophage expressing CD163 80, 81, 82. Although differentiation of monocytes into macrophages is likely to be terminal, macrophages have the ability to switch phenotype and functional characteristics in response to external signals.…”

Erratum: Inflammatory processes in cardiovascular disease: a route to targeted therapies

“…In mice, immuno-LCM coupled with downstream gene or protein expression analysis has been used to study lesional macrophages in various stages of atherogenesis, including atherosclerosis regression. The inflammatory state of plaque macrophages was shown to be dynamically regulated as the severity of disease varied 144 . In humans, studies using LCM on surgical plaque explants has also identified genes implicated in lipid metabolism (such as FABP4 and LEP) and activation of the adipokine/peroxisome proliferator-activator receptor (PPAR) signalling pathways 145 , as well as a repertoire of inflammatory gene 'signatures' 146 , that might be important in mechanistic staging.…”