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.
Project 1: Narrative Heightened inflammation and increased macrophage content of atherosclerotic plaques are associated with diabetes, and are believed to contribute to the relative resistance in diabetics to cardiovascular risk factor reduction by statin treatment. There is a need to better understand the mechanisms by which immune cells, particularly macrophages, accumulate in atherosclerotic plaques in diabetes in spite of plasma lipid lowering and to identify potential signals that promote the egress of these cells from an inflamed site in order to achieve the resolution of inflammation.
| Koelwyn, Graeme J; Corr, Emma M; Erbay, Ebru et al. (2018) Regulation of macrophage immunometabolism in atherosclerosis. Nat Immunol 19:526-537 |
| Moore, Kathryn J; Koplev, Simon; Fisher, Edward A et al. (2018) Macrophage Trafficking, Inflammatory Resolution, and Genomics in Atherosclerosis: JACC Macrophage in CVD Series (Part 2). J Am Coll Cardiol 72:2181-2197 |
| Hadi, Tarik; Boytard, Ludovic; Silvestro, Michele et al. (2018) Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells. Nat Commun 9:5022 |
| Barrett, Tessa J; Murphy, Andrew J; Goldberg, Ira J et al. (2017) Diabetes-mediated myelopoiesis and the relationship to cardiovascular risk. Ann N Y Acad Sci 1402:31-42 |
