Hyperglycemia, Aldose Reducatse & Murine Atherosclerosis

描述(由申请人提供)：虽然糖尿病与更多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高脂血症的发展或高血糖本身未能加速动脉粥样硬化，使得建立糖尿病大血管疾病动物模型的努力陷入混乱。我们假设老鼠缺乏一种基因，这种基因是允许高血糖对动脉的毒性作用所必需的。老鼠相对缺乏醛糖还原酶(AR)，这种酶将葡萄糖转化为山梨醇。我们发现，用链脲佐菌素(STZ)治疗糖尿病的低密度脂蛋白受体基因敲除小鼠(Ldlr-/-)可加速动脉粥样硬化，但存在表达人AR(HAR)的转基因。此外，杂合表达HAR的Ldlr-/-小鼠在STZ治疗后也有更大的病变大小。这项资助建议研究AR表达与小鼠动脉粥样硬化的关系。具体目的如下：目的1.探讨HAR在糖尿病大血管病变中的作用。.胰岛素缺乏和胰岛素抵抗的饮食和遗传模型将被交叉到有和没有HAR表达的Ldlr-/-背景上。目的2.探讨血管内皮细胞或巨噬细胞AR过度表达是否参与高血糖诱导的动脉粥样硬化。这些实验将使用骨髓移植和产生表达AR的转基因小鼠的新品系。目的3.探讨血管内皮细胞和/或巨噬细胞中AR的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之间的关系。这些信息随后将被用于研究体内的AR效应。我们预计，这些研究将阐明一种基因干预，这种干预导致糖尿病导致小鼠动脉粥样硬化的加速。这是有意义的，因为它将提供一个模型来研究这种并发症，并为预防糖尿病大血管疾病提供一个治疗靶点。

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.