Studies on receptors for modified LDL in human monocytes and macrophages. A link between diabetes and atherosclerosis?

Abstract

Type 2 diabetes increases the risk for cardiovascular disease three- to fourfold. Because of the rise in diabetes prevalence there is a need for a better understanding of the link between diabetes and atherosclerosis. This thesis deals with the monocyte/macrophage s property as a scavenger of modified low density lipoprotein (LDL) and abnormalities related to this property that may be of importance in the association between type 2 diabetes and atherosclerosis. The specific aims were to investigate 1) the regulation of scavenger receptor A by antioxidants, 2) the regulation of scavenger receptor CD36 by fatty acids and the thiazolidinedione darglitazone, and 3) if diabetes or impaired glucose tolerance is associated with abnormalities in the expression of monocytic receptors that are involved in atherogenesis. Scavenger receptor A was found to be down-regulated by the antioxidants N-acetylcysteine and a-tocopherol. The effect of incubation with N-acetylcysteine was the same in freshly isolated human monocytes, serum-differentiated macrophages and macrophages derived from atherosclerotic lesions. Thus it seems that the regulation of this gene is similar in macrophages in culture and in macrophages in atherosclerosis. In order to mimic the situation in type 2 diabetes human macrophages were incubated with free fatty acids. Fatty acids increased the expression of scavenger receptor CD36. This may lead to enhanced foam cell formation in diabetes. Darglitazone also up-regulated CD36, however it did not have this effect in the presence of fatty acids. In a population-based study 64-year old women with type 2 diabetes, impaired glucose tolerance and normal glucose tolerance were examined regarding the expression of monocytic surface receptors. Women with diabetes or impaired glucose tolerance had elevated expression of the Fcg-receptor CD64 and the common b2-integrin subunit CD18 on their monocytes and elevated circulating levels of oxidized LDL compared with women with normal glucose tolerance. Women with diabetes also had higher monocytic expression of CD14 and signs of a systemic inflammation, e.g. elevated levels of C-reactive protein, interleukin-6 and soluble adhesion molecules. The changes in monocytic receptor expression may confer increased propensity for activation and adhesion to the arterial wall and an increased uptake of LDL in immune complexes, leading to accelerated atherosclerosis in diabetes.In conclusion type 2 diabetes or metabolic disturbances associated with this disease can influence monocyte/macrophages in several ways, which may lead to accelerated atherosclerosis. Abnormalities in these cells may constitute a link between type 2 diabetes and atherosclerosis.