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.
Highlights
Patients with both type 1 and type 2 diabetes mellitus (T1DM, T2DM) have an increased risk of cardiovascular disease
As the NCD failed to reduce plasma cholesterol to levels required for regression (684±18 mg/dl after 4 weeks) we treated these mice with a single IV injection of the helperdependent adenovirus (HDAd)-LDL receptors (LDLR) virus to restore hepatic LDL receptor expression (Fig 1D)
Plasma triglyceride levels decreased with HDAd-LDLR treatment and those mice fed high fat diet (HFD) had slightly higher levels than mice fed low fat diet (LFD) (Fig 1E & 1F)
Summary
Patients with both type 1 and type 2 diabetes mellitus (T1DM, T2DM) have an increased risk of cardiovascular disease. With the large-scale use of statin medications, clinical studies have shown that over 60% of patients with marked reduction of circulating cholesterol concentrations have some reduction in plaque volume [1], but these changes reach at most, a few percent over 1–2 years. Diabetes partially negates this reduction in human atherosclerosis [2]. Convenient pre-clinical models to study the mechanisms by which diabetes adversely affects atherosclerosis, its regression, would be valuable
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