Diabetes Adversely Affects Macrophages During Atherosclerotic Plaque Regression in Mice

Abstract

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.

Resolution of inflammation: a new therapeutic frontier

“…In murine models, hyperglycaemia is associated with increased numbers of circulating monocytes -especially inflammatory LY6C + monocytes 179 -and polymorphonuclear cells (PMNs) 180 , which leads to their increased, proportional entry into plaques and consequent accelerated lesion progression. This seems to be replicated clinically: compared with individuals who have atherosclerosis alone, individuals with atherosclerosis and diabetes show impaired regression in response to cholesterolreducing therapies 181 , emphasizing the challenge of attempting to pharmacologically resolve clinical disease.…”

Hyperglycemia and Liver Ischemia Reperfusion Injury: A Role for the Advanced Glycation Endproduct and Its Receptor Pathway

“…As chronic hyperglycemia had been shown to promote myelopoiesis, increased numbers of neutrophils and monocytes were found in diabetic mice (31), which could result in an increase of their entry into inflammatory sites, leading to prolonged immune response and delayed lesion regression. In addition, tissue macrophages isolated from diabetic mice showed defective polarization into anti-inflammatory/tissue repairing M2 phenotypes (15,32), which would also lead to the persistence of tissue inflammation. Why was it not the case in our model?…”

Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression

“…In vitro, macrophages can polarize toward either the M1 or M2 state by treatment with IFN-γ and LPS, or IL-4 and IL-13, respectively. Notably, in regressing atherosclerotic plaques, we have observed that there is reduced expression of classical inflammatory genes characteristic of M1 macrophages, such as monocyte chemoattractant protein-1 (MCP-1), TNF-α, and iNOS, coincident with increased expression of genes encoding markers of alternatively activated, tissueremodeling M2 macrophages, such as arginase 1 (ARG1), mannose receptor (MR, also known as CD206), and IL-10 in CD68 + cells (2,3,5,12,13). Importantly, the enrichment of plaque CD68 + cells with markers of the M2 phenotype, though initially discovered in the transplant model (5,12), has been subsequently found in several different models of atherosclerosis regression (2-4), suggesting this represents a signature of plaque regression.…”