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

Abstract

We tested whether a high fat diet (HFD) containing the inflammatory dietary fatty acid palmitate or insulin deficient diabetes altered the remodeling of atherosclerotic plaques in LDL receptor knockout (Ldlr-/-) mice. Cholesterol reduction was achieved by using a helper-dependent adenovirus (HDAd) carrying the gene for the low-density lipoprotein receptor (Ldlr; HDAd-LDLR). After injection of the HDAd-LDLR, mice consuming either HFD, which led to insulin resistance but not hyperglycemia, or low fat diet (LFD), showed regression compared to baseline. However there was no difference between the two groups in terms of atherosclerotic lesion size, or CD68+ cell and lipid content. Because of the lack of effects of these two diets, we then tested whether viral-mediated cholesterol reduction would lead to defective regression in mice with greater hyperglycemia. In both normoglycemic and streptozotocin (STZ)-treated hyperglycemic mice, HDAd-LDLR significantly reduced plasma cholesterol levels, decreased atherosclerotic lesion size, reduced macrophage area and lipid content, and increased collagen content of plaque in the aortic sinus. However, reductions in anti-inflammatory and ER stress-related genes were less pronounced in STZ-diabetic mice compared to non-diabetic mice. In conclusion, HDAd-mediated Ldlr gene therapy is an effective and simple method to induce atherosclerosis regression in Ldlr-/- mice in different metabolic states.

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

“…The control group received concentration‐matched BSA alone. A third group was switched to standard chow diet, in order to lower plasma cholesterol and promote lesion regression 39. At the end of the sixth week, lymphatic function assays were performed and blood and lymph were collected under anesthetic conditions.…”

“…A third group was switched to standard chow diet, in order to lower plasma cholesterol and promote lesion regression. 39 At the end of the sixth week, lymphatic function assays were performed and blood and lymph were collected under anesthetic conditions. Following this, mice were euthanized by cardiac puncture following ketamine anesthesia (100 mg/mL ketamine administered at 0.10 mL/10 g of body weight), or by carbon dioxide (CO 2 ), and were perfused with 15 mL PBS.…”

Macrophage Phenotype and Function in Different Stages of Atherosclerosis

“…Regression of lesions can be induced in hyperlipidemic mouse models by aggressive lipid lowering and in diabetic mice by blood glucose lowering 127-130 . The regression in these models is characterized by reduced lesion macrophage content (Figure 4) and altered gene expression in the remaining CD68-positive cells.…”

Monocyte-Macrophages and T Cells in Atherosclerosis

“…Indeed, largely due to the epidemic of obesity and insulin resistance, atherosclerotic vascular disease remains the leading cause of death in the industrialized world, and its prevalence is expected to rise over the next 20 years (Go et al, 2013; Behn and Ur, 2006; American Heart Association and RTI International, 2015). In this regard, a topic of great interest moving forward is how insulin resistance might affect the immune processes discussed in this review and thereby exacerbate atherosclerosis (Han et al, 2006; Kanter et al, 2012; Nagareddy et al, 2013; Willecke et al., 2015). Moreover, as the number of patients being treated with PCSK9 inhibitors increases, we may have an opportunity to learn how lowering cholesterol below the concentrations achieved with statins alters immune parameters of atherosclerosis, even in the face of the obesity epidemic (Dullaart, 2017; Boren and Williams, 2016).…”