Cell Signaling: Macrovascular Complications of Diabetes

描述（由申请人提供）：大多数糖尿病患者死于动脉粥样硬化引起的心血管疾病。高血糖症和高胆固醇血症被认为是导致心血管疾病增加的原因。迄今为止，没有动物模型能够区分高血糖和高甘油三酯血症对斑块进展的贡献。晚期斑块中巨噬细胞的积聚可能导致斑块进展。我们推测，糖尿病高脂血症相关的脂肪酸负荷增加通过刺激巨噬细胞积聚和蛋白酶分泌导致斑块进展。在这次竞争性续约中，我们建议解决以下问题： 1)糖尿病诱导的高甘油三酯血症是否是既存病变进展所必需的？我们已经建立了一种糖尿病加速动脉粥样硬化的小鼠模型，可用于分离高血糖和高甘油三酯血症对斑块进展的影响。将研究糖尿病诱导的高胆固醇血症对既存斑块的影响。 2)在高血糖的情况下降低高血糖是否能预防糖尿病加速的斑块进展？我们建议使用辅助依赖性腺病毒载体在糖尿病小鼠肝脏中过表达VLDL受体，从而使高脂血症正常化。 3)脂肪酸负荷增加是否会导致体外巨噬细胞积聚和蛋白酶分泌增加？我们建议将分离的巨噬细胞暴露于增加或减少的脂肪酸负荷。 4)巨噬细胞中脂肪酸负荷增加是否是斑块进展所必需和充分的？我们建议使用巨噬细胞选择性逆转录病毒载体在巨噬细胞中过表达酰基辅酶A合成酶1（Acsl1），并产生巨噬细胞靶向Acsl1缺失的小鼠。将研究对既存病变进展的影响。 我们期望这些研究将显著增加我们对高胆固醇血症在糖尿病斑块进展中的作用的理解，并可能为开发可预防或减缓糖尿病心血管并发症的药物或基因疗法提供必要的基本信息。

DESCRIPTION (provided by applicant): A majority of people with diabetes die of cardiovascular disease caused by atherosclerosis. Both hyperglycemia and hypertriglyceridemia are believed to contribute to the increased cardiovascular disease. No animal model to date has been able to distinguish between the contributions of hyperglycemia and hypertriglyceridemia to plaque progression. Accumulation of macrophages in advanced plaques is likely to lead to plaque progression. We hypothesize that the increased fatty acid load associated with hypertriglyceridemia in diabetes causes plaque progression by stimulating macrophage accumulation and secretion of proteases. In this competitive renewal, we propose to address the following questions: 1) Is diabetes-induced hypertriglyceridemia necessary for progression of pre-existing lesions? We have developed a mouse model of diabetes-accelerated atherosclerosis that can be used to separate effects of hyperglycemia and hypertriglyceridemia on plaque progression. The effect of diabetes-induced hypertriglyceridemia on pre-existing plaques will be studied. 2) Does lowering of hypertriglyceridemia in the presence of hyperglycemia prevent diabetes-accelerated plaque progression? We propose to use a helper-dependent adenoviral vector to overexpress the VLDL receptor in livers of diabetic mice, thereby normalizing hypertriglyceridemia. 3) Does increased fatty acid load lead to increased macrophage accumulation and protease secretion ex vivo? We propose to expose isolated macrophages to increased or decreased fatty acid load. 4) Is increased fatty acid load in macrophages necessary and sufficient for plaque progression? We propose use a macrophage-selective retroviral vector to overexpress acyl-CoA synthetase 1 (Acsl1) in macrophages, and also to generate a mouse with macrophage-targeted deletion on Acsl1. The effect on progression of pre-existing lesions will be investigated. We expect that these studies will significantly increase our understanding of the role of hypertriglyceridemia in plaque progression in diabetes, and may provide the basic information necessary for development of drugs or gene therapies that can prevent or slow down cardiovascular complications of diabetes.