Acyl-CoAs and Lesion Initiation in Diabetes

描述：这些研究的目的是确定在高血糖状态下导致动脉粥样硬化病变加速发生的机制。我们将集中于内皮细胞和巨噬细胞--在病变启动中最重要的两种细胞类型。这些实验将在分离的小鼠内皮细胞和巨噬细胞中进行，并在转基因低密度脂蛋白受体缺陷小鼠模型中进行，在该模型中，病毒可以诱导1型糖尿病(LDLR-/-；GP小鼠)。在初步实验的基础上，我们假设高血糖的主要致动脉粥样硬化作用依赖于通过增加长链酰基-辅酶A合成酶1(ACSM)的活性而增加脂肪酰基-COAs的形成。我们建议通过对内皮细胞和巨噬细胞中Acsl1表达水平的靶向调节，直接测试酰基辅酶A合成在葡萄糖和糖尿病对病变启动的影响中的作用。我们的目标是解决以下三个问题：1)酰辅酶A合成在葡萄糖刺激培养的内皮细胞和巨噬细胞产生炎症分子中是否具有中心重要性？2)巨噬细胞中酰辅酶A合成的增加是否与糖尿病对LDLR-/-；GP小鼠的炎症介质和病变启动的影响相似？3)抑制内皮细胞或巨噬细胞的酰基辅酶A合成是否延缓了糖尿病动脉粥样硬化加速的小鼠模型的病变启动？这些研究将增加我们对高血糖条件下糖尿病加速病变启动的分子机制的理解。这种机制的识别可能被用来开发针对1型糖尿病心血管并发症的药物。

DESCRIPTION: The studies proposed aim to identify mechanisms leading to accelerated atherosclerotic lesion initiation in the presence of hyperglycemia. We will focus on endothelial cells and macrophages-the two most important cell types in lesion initiation. The experiments will be carried out in isolated mouse endothelial cells and macrophages, and in a transgenic LDL receptor-deficient mouse model in which type 1 diabetes can be induced by a virus (the LDLR-/-;GP mouse). Based on preliminary experiments, we hypothesize that the main atherogenic effects of hyperglycemia are dependent on increased formation of fatty acyl-CoAs, through increased activity of long chain acyl-CoA synthetase 1 (AcsM). We propose to directly test the contribution acyl-CoA synthesis in the effects of glucose and diabetes on lesion initiation by targeted modulation of expression levels of Acsl1 in endothelial cells and macrophages. The goal is to address the following three questions: 1) Is acyl-CoA synthesis of central importance in glucose-stimulated production of inflammatory molecules by cultured endothelial cells and macrophages?; 2) Does increased acyl-CoA synthesis in macrophages mimic the effects of diabetes on inflammatory mediators and lesion initiation in LDLR-/-;GP mice?; 3) Does inhibition of acyl-CoA synthesis in endothelial cells or macrophages retard lesion initiation in our mouse model of accelerated diabetic atherosclerosis? These studies will increase our understanding of the molecular mechanisms involved in diabetes-accelerated lesion initiation under hyperglycemic conditions. Identification of such mechanisms might be used to develop drugs to target cardiovascular complications of type 1 diabetes.