Project 1: Summary The relationship between diabetes and atherosclerosis is well established. Indeed, people with diabetes are overwhelmingly likely to suffer from coronary heart disease (CHD). Though the relative risk of CHD falls with statin treatment of diabetics, the absolute risk remains elevated compared to non-diabetics, consistent with our finding in animal models that diabetes impairs plaque regression after lipid lowering. In Project 1, we propose to use these models to determine how diabetes maintains in atherosclerotic plaques high levels of macrophages and their inflammatory state despite aggressive reductions in hyperlipidemia. A major goal is to determine the kinetic bases for the increased content of plaque macrophages in diabetic atherosclerotic mice after lipid reduction. The possibilities include changes in the recruitment of monocytes to the plaques, the retention or chemostasis of plaque macrophages, the degree of macrophage apoptosis or efferocytosis, and the proliferation of macrophages in the plaques. We will extend our initial studies in mice with type 1 diabetes (T1D) to mice with diet-induced obesity (DIO) and insulin-resistance (IR) as a model of the IR, high-CHD risk states (metabolic syndrome, type 2 diabetes), prevalent in the US population. We will also test the roles of candidate factors in the maladaptive macrophage responses to diabetes despite lipid lowering. These include netrin-1, a macrophage retention molecule (also to be studied in adipose tissue under Project 2), RAGE, the receptor for advanced glycation endproducts (which we find also promotes macrophage retention), and ACSL1, an inflammatory factor induced by hyperglycemia. For the first 2, we will explore their translational potential. We will also employ unbiased, genome-based, bioinformatic approaches to uncover new factors/pathways that regulate macrophage content and inflammation not only in plaques, but in combination with Projects 2 and 3, also in adipose tissue in DIO mice.