Hyperglycemia, Aldose Reducatse & Murine Atherosclerosis

描述（由申请人提供）：虽然糖尿病与动脉粥样硬化的发展有关，但其原因尚不完全清楚。在过去的十年中，由于许多糖尿病小鼠出现高脂血症或高血糖不能单独加速动脉粥样硬化，建立糖尿病大血管疾病动物模型的努力受到了干扰。我们假设小鼠缺乏一种基因，这种基因需要允许高血糖对动脉产生毒性作用。小鼠醛糖还原酶（AR）相对缺乏，醛糖还原酶是将葡萄糖转化为山梨醇的酶。我们发现LDL受体敲除小鼠（Ldlr-/-）接受链脲佐菌素（STZ）治疗后，当存在表达人类AR （hAR）的转基因时，其动脉粥样硬化加速。此外，stz处理的杂合子表达ha的Ldlr-/-小鼠也有更大的病变大小。本课题拟研究AR表达与小鼠动脉粥样硬化的关系。具体目标如下：目标1。目的：探讨hAR表达对糖尿病大血管病变的影响。胰岛素缺乏和胰岛素抵抗的饮食和遗传模型将交叉到有或没有hAR表达的Ldlr-/-背景上。目标2。评估内皮细胞或巨噬细胞中AR过表达是否介导高血糖诱导的动脉粥样硬化。这些实验将采用骨髓移植和生产转基因AR表达小鼠的新品系。目标3。确定内皮细胞和/或巨噬细胞中的AR表达是否影响高血糖时的炎症过程。组织培养实验将探索hAR表达与炎症和细胞胆固醇摄取相关的途径。这些信息随后将用于研究体内ar效应。这些研究将，我们期望，说明遗传干预导致可重复的糖尿病介导的小鼠动脉粥样硬化加速。这将为研究该并发症提供模型，并为预防糖尿病大血管疾病提供治疗靶点，具有重要意义。

DESCRIPTION (provided by applicant): Although diabetes mellitus is associated with the development of more atherosclerosis, the reasons for this are not entirely understood. Efforts during the past decade to develop animal models of diabetic macrovascular disease were confounded by the development of hyperlipidemia in many diabetic mice or the failure of hyperglycemia alone to accelerate atherosclerosis. We hypothesized that mice were deficient in a gene required to allow the toxic effects of hyperglycemia on arteries. Mice are relatively deficient in aldose reductase (AR), the enzyme that converts glucose to sorbitol. We discovered that LDL receptor knockout mice (Ldlr-/-) made diabetic with streptozotocin (STZ) treatment have accelerated atherosclerosis when a transgene expressing human AR (hAR) is present. Moreover, heterozygous hAR-expressing Ldlr-/- mice also have greater lesion size with STZ-treatment. This grant proposes to study the relationship between AR expression and murine atherosclerosis. The specific aims are as follows: Aim 1. To determine the effects of hAR expression on macrovascular disease in diabetic models. .Dietary and genetic models of insulin deficiency and insulin resistance will be crossed onto the Ldlr-/- background with and without hAR expression. Aim 2. To assess whether AR over-expression in endothelial cells or macrophages mediates hyperglycemia-induced atherosclerosis. These experiments will employ transplantation of bone marrow and production of new lines of transgenic AR expressing mice. Aim 3. To determine whether AR expression in endothelial cells and/or macrophages affects inflammatory processes in the setting of hyperglycemia. Tissue culture experiments will explore pathways relating hAR expression to inflammation and cellular cholesterol uptake. This information will then be used to study AR-effects in vivo. These studies will, we expect, illustrate a genetic intervention that leads to reproducible diabetes-mediated acceleration of atherosclerosis in mice. This is significant because it will provide for a model to study this complication and suggest a therapeutic target for prevention of diabetic macrovascular disease.