Hyperglycemia Impairs Atherosclerosis Regression in Mice

Abstract

Diabetic patients are known to be more susceptible to atherosclerosis and its associated cardiovascular complications. However, the effects of hyperglycemia on atherosclerosis regression remain unclear. We hypothesized that hyperglycemia impairs atherosclerosis regression by modulating the biological function of lesional macrophages. HypoE (Apoe(h/h)Mx1-Cre) mice express low levels of apolipoprotein E (apoE) and develop atherosclerosis when fed a high-fat diet. Atherosclerosis regression occurs in these mice upon plasma lipid lowering induced by a change in diet and the restoration of apoE expression. We examined the morphological characteristics of regressed lesions and assessed the biological function of lesional macrophages isolated with laser-capture microdissection in euglycemic and hyperglycemic HypoE mice. Hyperglycemia induced by streptozotocin treatment impaired lesion size reduction (36% versus 14%) and lipid loss (38% versus 26%) after the reversal of hyperlipidemia. However, decreases in lesional macrophage content and remodeling in both groups of mice were similar. Gene expression analysis revealed that hyperglycemia impaired cholesterol transport by modulating ATP-binding cassette A1, ATP-binding cassette G1, scavenger receptor class B family member (CD36), scavenger receptor class B1, and wound healing pathways in lesional macrophages during atherosclerosis regression. Hyperglycemia impairs both reduction in size and loss of lipids from atherosclerotic lesions upon plasma lipid lowering without significantly affecting the remodeling of the vascular wall.

Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice

“…However, calculating the percentage change in the regression groups versus their respective baseline groups showed that both reduction in lesion size and CD68+ areas were significantly less alleviated in HDAd-LDLR treated STZ-diabetic mice compared to the non-diabetic mice (51% lesion size reduction in non-diabetic mice vs. 36% in STZ-diabetic mice, and reduction of 77% CD68+ cells in non-diabetic mice vs. 57% in STZ-diabetic mice), consistent with our previous study [ 8 ]. Using hypomorphic ApoE mice, Gaudreault et al also reported an impaired lesion size reduction with STZ-diabetes, but in contrast to our past and present results, no differences were noted in the cell composition of the atherosclerotic lesion [ 42 ]. Besides the use of different regression models, this difference might be due to different changes in lipoprotein composition (more VLDL-cholesterol reduction) and degree of cholesterol reduction, with HDAd-LDLR treatment being more effective.…”

High glucose macrophage exosomes enhance atherosclerosis by driving cellular proliferation & hematopoiesis

“…Numerous studies have reported changes in circulating microRNA levels associated with accelerated atherosclerotic disease in diabetes ( de Candia et al., 2017 ; Zampetaki et al., 2010 ). As we and others ( Gaudreault et al., 2013 ; Nagareddy et al., 2013 ) observed that myeloid cells are impacted by hyperglycemia, we performed microRNA sequencing on Ly-6C hi monocytes and macrophages isolated from mouse models of hyperglycemia that included the STZ-induced and spontaneous Akita mouse models of diabetes.…”

Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice

“…Cardiovascular disease (CVD) and diabetes are both associated with leukocytosis (1,2). We and others have previously reported that hyperglycemia in mice impaired the resolution of atherosclerosis after lipid lowering (3,4). Hyperglycemia also stimulated myelopoiesis in the mice, which increased circulating levels of monocytes and neutrophils and their entry into atherosclerotic plaques (5)(6)(7).…”