S100A9 and S100A8 in Diabetes and Atherosclerosis

描述(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。在探索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从糖尿病小鼠的巨噬细胞中分泌增加，并且免疫活性S100A9在糖尿病小鼠的动脉粥样硬化病变中含量丰富，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型糖尿病患者分离的单核细胞表达高水平的S100A9，增加了S100A8/A9在糖尿病血管病变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性群体，并且这一群体分泌高水平的S100A8/A9。我们进一步假设S100A8/A9通过两种机制促进1型糖尿病的动脉粥样硬化：i)调节巨噬细胞激活状态；ii)动脉壁局部炎症效应。拟议的实验将在分离的小鼠巨噬细胞、S100A9缺陷小鼠以及转基因低密度脂蛋白受体缺陷小鼠动脉粥样硬化模型中进行，在该模型中，1型糖尿病可以由病毒诱导(LDLR-/-；GP小鼠)。我们建议直接测试S100A8/A9在炎症和糖尿病加速的动脉粥样硬化中的作用。我们的目标是解决以下三个问题：1)1型糖尿病是否促进炎性巨噬细胞在组织中的聚集？2)S100A8/A9是否调节1型糖尿病的巨噬细胞激活？3)S100A8/A9是否促进1型糖尿病病变的启动和/或进展？ 公共卫生相关性：这些研究将增加我们对1型糖尿病加速动脉粥样硬化病变启动和进展为晚期病变所涉及的分子和细胞机制的理解。识别这种机制可能有助于开发针对与1型糖尿病相关的心血管并发症的治疗策略。

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.