S100A9 and S100A8 in Diabetes and Atherosclerosis

描述（由申请人提供）：动脉粥样硬化引起的心血管并发症是1型糖尿病患者死亡的主要原因。在寻找1型糖尿病小鼠模型中糖尿病加速动脉粥样硬化的机制时，我们发现促炎蛋白S100A9在糖尿病小鼠巨噬细胞中分泌水平升高，并且免疫反应性S100A9在糖尿病小鼠动脉粥样硬化病变中丰富，并与斑块内出血相关。有趣的是，最近的研究发现S100A9及其结合伙伴S100A8是人类心血管事件的生物标志物。从1型糖尿病患者中分离的单核细胞表达高水平的S100A9，这提高了S100A8/A9在糖尿病血管疾病中发挥重要作用的可能性。基于这些观察和初步研究，我们假设1型糖尿病促进组织中巨噬细胞的炎症群，并且该群分泌高水平的S100A8/A9。我们进一步假设S100A8/A9通过两种机制促进1型糖尿病动脉粥样硬化：i)调节巨噬细胞激活状态；ii)动脉壁局部炎症作用。该实验将在分离的小鼠巨噬细胞、s100a9缺陷小鼠和可由病毒诱导1型糖尿病的转基因LDL受体缺陷小鼠模型（LDLR-/-；GP小鼠）中进行。我们建议直接检测S100A8/A9在炎症和糖尿病加速动脉粥样硬化中的作用。目标是解决以下三个问题：1)1型糖尿病是否促进炎症性巨噬细胞在组织中的积累？2) S100A8/A9是否调节1型糖尿病中巨噬细胞的活化？3) S100A8/A9是否促进1型糖尿病病变的发生和/或进展？

DESCRIPTION (provided by applicant): 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? PUBLIC HEALTH RELEVANCE: 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.