Book Description

The severity of atherosclerosis, which underlies the majority of cardiovascular disease, is determined by a wide variety of factors. Though many of these factors are well studied, a complete understanding of how to best slow or reverse development of atherosclerosis is lacking. Blood glucose is positively associated with an increased incidence of cardiovascular disease in several studies. However, elevations in blood glucose in humans are often accompanied by additional cardiovascular disease risk factors such as elevated lipids in people with concurrent metabolic syndrome and/or increased circulating cytokines in people with diabetes. In the following body of work, the contribution of cell type-specific dysregulation of glucose uptake and fatty acid handling to atherosclerosis was investigated in models of metabolic syndrome and diabetes. Features of metabolic syndrome (including weight gain, increased plasma lipids and elevated blood glucose) can be induced in mice by combining low-density lipoprotein receptor (LDLR) deficiency with a high fat, high carbohydrate diet with added cholesterol. By using a mouse model of metabolic syndrome, factors of metabolic syndrome could be held constant and additional glucose uptake was introduced in a cell-type specific manner. Here we hypothesized that smooth muscle cells were preferentially influenced by increased glycolytic flux leading to accelerated atherosclerosis in a model of metabolic syndrome. Increased glucose uptake in smooth muscle cells (SMCs) or macrophages in vivo was made possible by specific overexpression of the insulin-independent glucose transporter, GLUT1, in either of these cell types. Increased glucose uptake alone in either of these cell types did not facilitate atherosclerosis initiation or progression. However, increased glucose uptake in SMCs in combination with traits of metabolic syndrome allowed accelerated development of lesions, which were larger, contained more free cholesterol and had increased lesion SMC and glycosaminoglycan content. This effect was specific to SMCs over myeloid cells. In an additional study using the same metabolic syndrome model, mice having GLUT1 overexpressed in myeloid cells did not differ from controls. The phenotype of type 1 diabetes mellitus includes both increased markers of systemic inflammation and high blood glucose, both of which have been the focus of several recent publications. For studies of diabetes mellitus in mice, glucose is increased and cell-type specific modifications are made to reduce the inflammatory potential of immune cells or their target receptors. It has previously been shown that enzymes involved in intracellular fatty acid handling are increased in myeloid cells by diabetes, and that modifications to fatty acid metabolism in macrophages can block inflammation and atherosclerosis without lowering blood glucose. These studies suggest that fatty acid handling is a strong factor in acceleration of the disease, at least in mice. Here we investigated the role of acyl-CoA thioesterases 7 (ACOT7) in diabetes. The role of this enzyme is poorly understood. We hypothesized that ACOT7 is induced in macrophages by diabetes and that it contributes to diabetes-associated macrophage inflammation and atherosclerosis. ACOT7 was increased in macrophages in a mouse model of diabetes. Overexpression of ACOT7 increased inflammatory mediators in activated macrophages in vitro. However its deletion from bone marrow derived cells in vivo had only a minor reducing effect on inflammatory mediators and did not reduce diabetes-accelerated atherosclerosis. Together, these studies provide novel information on the role of glucose and fatty acid handling in cell types involved in atherosclerosis associated with metabolic syndrome and diabetes. Cell-type specific modifications in combination with systemic drivers of atherosclerosis can fine-tune knowledge not only of which pathways show promise as therapeutic targets, but which cell types should be targeted for maximal effectiveness of future treatments.