Cardiovascular complications caused by atherosclerosis are the major cause of death in patients with type 1 diabetes. While searching for a mechanism of diabetes-accelerated atherosclerosis in a mouse model of type1diabetes, we discovered that the pro-inflammatory protein S100A9 is secreted at increased levels from macrophages from diabetic mice, and that immunoreactive S100A9 is abundant in atherosclerotic lesions from diabetic mice and correlates with intraplaque hemorrhage. Interestingly, recent studies identify S100A9 and its binding partner S100A8 as biomarkers of cardiovascular events in humans. Monocytes isolated from humans with type 1 diabetes express high levels of S100A9, raising the possibility that S100A8/A9 plays an important role in diabetic vascular disease. Based on these observations and preliminary studies, we hypothesize that type 1 diabetes promotes an inflammatory population of macrophages in tissues, and that this population secretes elevated levels of S100A8/A9. We further hypothesize that S100A8/A9 promotes atherosclerosis in type 1 diabetes by two mechanisms: i) regulation of macrophage activation state;and ii) local inflammatory effects in the artery wall. The proposed experiments will be carried out in isolated mouse macrophages, in an S100A9-deficient mouse, and in a transgenic LDL receptor-deficient mouse model of atherosclerosis in which type 1 diabetes can be induced by a virus (the LDLR-/-;GP mouse). We propose to directly test the contribution of S100A8/A9 in inflammation and diabetes-accelerated atherosclerosis. The goal is to address the following three questions: 1) Does type 1 diabetes promote accumulation of inflammatory macrophages in tissues? 2) Does S100A8/A9 regulate macrophage activation in type 1 diabetes? 3) Does S100A8/A9 promote lesion initiation and/or progression in type 1 diabetes?
These studies will increase our understanding of the molecular and cellular mechanisms involved in type 1 diabetes-accelerated atherosclerotic lesion initiation and progression to advanced lesions. Identification of such mechanisms might help develop treatment strategies to target cardiovascular complications associated with type 1 diabetes.
|Rune, Ida; Rolin, Bidda; Larsen, Christian et al. (2016) Modulating the Gut Microbiota Improves Glucose Tolerance, Lipoprotein Profile and Atherosclerotic Plaque Development in ApoE-Deficient Mice. PLoS One 11:e0146439|
|Bornfeldt, Karin E (2015) Uncomplicating the Macrovascular Complications of Diabetes: The 2014 Edwin Bierman Award Lecture. Diabetes 64:2689-97|
|Vallerie, Sara N; Bornfeldt, Karin E (2015) GPIHBP1: two get tangled. Circ Res 116:560-2|
|Pamir, Nathalie; Liu, Ning-Chun; Irwin, Angela et al. (2015) Granulocyte/Macrophage Colony-stimulating Factor-dependent Dendritic Cells Restrain Lean Adipose Tissue Expansion. J Biol Chem 290:14656-67|
|Willecke, Florian; Yuan, Chujun; Oka, Kazuhiro et al. (2015) Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice. PLoS One 10:e0128996|
|Wall, Valerie Z; Bornfeldt, Karin E (2014) Arterial smooth muscle. Arterioscler Thromb Vasc Biol 34:2175-9|
|Bornfeldt, Karin E (2014) 2013 Russell Ross memorial lecture in vascular biology: cellular and molecular mechanisms of diabetes mellitus-accelerated atherosclerosis. Arterioscler Thromb Vasc Biol 34:705-14|
|Lee, Jung-Ting; Pamir, Nathalie; Liu, Ning-Chun et al. (2014) Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase. Endocrinology 155:3409-20|
|Nishizawa, Tomohiro; Kanter, Jenny E; Kramer, Farah et al. (2014) Testing the role of myeloid cell glucose flux in inflammation and atherosclerosis. Cell Rep 7:356-365|
|Nagareddy, Prabhakara R; Kraakman, Michael; Masters, Seth L et al. (2014) Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab 19:821-35|
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