Cell Signaling: Macrovascular Complications of Diabetes

描述（由申请人提供）：糖尿病促进人类动脉粥样硬化，大大增加患心血管疾病的风险。令人信服的临床数据表明，改善生命早期的血糖控制对1型糖尿病受试者的心血管事件具有长期有益的影响。巨噬细胞可能在糖尿病对动脉粥样硬化的刺激作用中起关键作用。我们的初步研究表明，除了刺激促炎反应外，糖尿病和葡萄糖水平升高还导致巨噬细胞中脂肪酸分解酶（长链酰基辅酶A合成酶1; ACSL 1）的表达增加，表明巨噬细胞中的炎症能力与ACSL 1之间存在密切联系，糖尿病和高血糖状态。引人注目的是，糖尿病对动脉粥样硬化病变形成的刺激作用可以通过删除骨髓细胞中的ACSL 1而完全预防。在非糖尿病小鼠中没有观察到这种效应，这表明所发现的机制对糖尿病具有选择性。ACSL 1缺乏的保护作用与巨噬细胞释放促炎介质减少相关。该项目的总体假设是，糖尿病主要通过增加巨噬细胞中的葡萄糖摄取来促进动脉粥样硬化，这促进了需要ACSL 1的炎性巨噬细胞表型。我们的目标是解决两个问题：（1）。巨噬细胞葡萄糖摄取增加是否通过需要ACSL 1的机制增强其促炎能力和动脉粥样硬化？2）。葡萄糖介导的巨噬细胞活化的ACSL 1依赖性机制是什么？ 公共卫生相关性：这些研究将增加我们对糖尿病加速动脉粥样硬化和心血管疾病的分子和细胞机制的理解。对这些机制的识别可能有助于制定针对心血管并发症和其他与糖尿病相关的并发症的治疗策略。

DESCRIPTION (provided by applicant): Diabetes promotes atherosclerosis in humans, greatly increasing the risk of developing cardiovascular disease. Compelling clinical data show that improving glycemic control early in life has long-term beneficial effects on cardiovascular events in human subjects with type 1 diabetes. Macrophages are likely to play a key role in the stimulatory effects of diabetes on atherosclerosis. Our preliminary studies demonstrate that in addition to stimulating a pro-inflammatory response, diabetes and elevated glucose levels lead to an increased expression of an enzyme that esterifies fatty acids (long-chain acyl-CoA synthetase 1; ACSL1) in macrophages, suggesting a close connection between the inflammatory capacity and ACSL1 in macrophages, diabetes and states of hyperglycemia. Strikingly, the stimulatory effects of diabetes on atherosclerotic lesion formation can be completely prevented by deleting ACSL1 in myeloid cells. No such effect is seen in non-diabetic mice, suggesting that the discovered mechanism is selective for diabetes. The protective effect of ACSL1-deficiency correlates with a reduced release of pro-inflammatory mediators from macrophages. The overall hypothesis of this project is that diabetes promotes atherosclerosis largely through increased glucose uptake in macrophages, which promotes an inflammatory macrophage phenotype that requires ACSL1. Our goal for the proposed project is to address two questions: 1). Does increased glucose uptake in macrophages enhance their pro-inflammatory capacity and atherosclerosis through a mechanism that requires ACSL1?; 2). What is the ACSL1-dependent mechanism of glucose-mediated macrophage activation? PUBLIC HEALTH RELEVANCE: These studies will increase our understanding of the molecular and cellular mechanisms involved in diabetes- accelerated atherosclerosis and cardiovascular disease. Identification of such mechanisms might help develop treatment strategies to target cardiovascular complications, and other complications, associated with diabetes.