Abstract 481: Diabetic Hyperglycemia Accelerates Atherosclerosis by Driving Adaptive Immunity in Mice with Similar Hyperlipidemia
Hyperglycemia is recognized to accelerate atherosclerosis and its complications among human diabetic individuals. Although the participation of monocytes and macrophages in the pathogenesis of diabetic atherosclerosis is well established, a role for adaptive immunity is not well understood. Unfortunately, hyperglycemia raises plasma lipids in mice fed a high-fat diet that can independently activate immune cells to enhance atherosclerosis. We have overcome this impediment with studies of hypomorphic apoE (Apoeh/h) mice deficient in LDL receptor expression. Apoeh/hLdlr-/- mice fed a chow diet display plasma cholesterol levels of 650+/-50 mg/dl by 4 months of age, and do not display significantly more hyperlipidemia when they are made hyperglycemic with streptozotocin. Our studies show that 4 weeks of hyperglycemia with an average blood glucose level of 400 mg/dl results in marked leukocytosis among 24 week-old Apoeh/hLdlr-/- mice continually fed a chow diet. Levels of blood Ly6Chigh monocytes increased by two fold and displayed enhanced cellular oxidative stress similar to primary macrophages cultured in high glucose that displayed increased NF-kB activation. Interestingly, we also noted that levels of circulating CD4+ T cells increased by twofold. A similar pattern of leukocyte expansion was also noted in the spleen, including a twofold expansion in CD11c+ dendritic cells (DC) and CD4+ T cells. We also noted evidence of DC activation as revealed by increased cell surface expression of the co-stimulatory molecule CD80 that participates in the activation and expansion of T cells. At the level of the vessel wall, we noted that 4 weeks of hyperglycemia resulted in a substantial increase in atherosclerosis in the aortic root as revealed by Oil Red O staining. Using the aorta digest method, we noted a 4-fold increase in macrophages and 3-fold increase in CD3+ T cells in the abdominal aorta. Collectively, our results show that hyperglycemia accelerates atherosclerosis in hyperlipidemic mice by enhancing adaptive immune cell-driven inflammation, and ongoing studies are exploring mechanisms responsible for this effect.
Author Disclosures: R.L. Raffai: None. F. Luk: None. K. Li: None.
- © 2015 by American Heart Association, Inc.