MITOCHONDRIAL DYSFUNCTION IN THE DIABETIC ENDOTHELIUM

项目SuIVIMARY(请参阅说明)： 2型糖尿病是心血管疾病的一个主要且日益普遍的危险因素。尽管存在严重的风险因素和血糖控制，但风险依然存在。糖尿病血管病变的一个关键机制是内皮功能障碍的发展。对糖尿病血管内皮细胞功能障碍机制的更好理解可能会刺激患者管理的新方法。 先前的实验研究将线粒体功能障碍与糖尿病血管疾病的发病机制联系起来。 升高的葡萄糖和游离脂肪酸水平刺激线粒体产生活性氧物种(ROS)，损害生物发生和动力学。这些情况降低了一氧化氮的可获得性，并激活了内皮细胞。虽然已经在患者的骨骼肌中观察到线粒体功能的异常，但在人类糖尿病中，线粒体功能障碍与血管疾病之间的联系仍然知之甚少。我们已经开发了方法学来研究新鲜分离的血管组织(皮下脂肪中的静脉内皮细胞和小动脉)和更容易获得的血液单个核细胞中线粒体功能的特定方面。我们的初步研究表明，与内皮功能障碍相关的线粒体ROS增加，线粒体质量减少，线粒体网络丢失。 在目标1中，我们将分离的内皮细胞和单个核细胞的线粒体功能与200名患者和对照组的前臂内皮功能相关联。在目标2中，我们将通过分离小动脉和皮下脂肪来研究线粒体和内皮功能障碍之间的机制联系，并使用器官小室方法和视频显微镜来测量特定的线粒体激动剂/拮抗剂对内皮依赖性血管扩张的影响。在目标3中，我们将确定旨在增加线粒体生物发生和动力学的干预措施(白藜芦醇)是否具有良好的效果 我们对50名糖尿病患者进行了一项随机、安慰剂对照的交叉研究，测量血管内皮细胞和线粒体的功能。 我们建议的研究与该计划项目的总体主题非常吻合，我们希望获得有关线粒体功能障碍对血管损伤的贡献的新信息，这将使我们更接近于确定降低糖尿病心血管风险的最佳治疗策略。

PROJECT SUIVIMARY (See instructions): Type 2 diabetes mellitus is a major and increasingly prevalent risk factor for cardiovascular disease. Risk persists despite intensive risk factor and glucose control. A key mechanism in diabetic vascular disease is the development of endothelial dysfunction. An improved understanding ofthe mechanisms of endothelial dysfunction in diabetes could stimulate new approaches for patient management. Prior experimental studies link mitochondrial dysfunction to the pathogenesis of diabetic vascular disease. Elevated glucose and free fatty acid levels stimulate mitochondrial production of reactive oxygen species (ROS) and impair biogenesis and dynamics. These conditions reduce nitric oxide availability and activate endothelial cells. Although abnormalities of mitochondrial function have been observed in skeletal muscle from patients, the connections between mitochondrial dysfunction and vascular disease remain pooriy understood in human diabetes. We have developed methodology to study specific aspects of mitochondrial function in freshly isolated vascular tissue (venous endothelial cells and arterioles from subcutaneous fat) and in more accessible blood mononuclear cells. Our preliminary studies show increased mitochondrial ROS, decreased mitochondrial mass, and loss of mitochondrial networks that relate to endothelial dysfunction. In Aim 1, we will correlate mitochondrial function in isolated endothelial cells and mononuclear cells to endothelial function in the forearm of 200 patients and controls. In Aim 2, we will investigate the mechanistic links between mitochondrial and endothelial dysfunction by isolating arterioles from subcutaneous fat and use organ chamber methodology and video microscopy to measure the effects of specific mitochondrial agonists/antagonists on endothelium-dependent vasodilation. In Aim 3, we will determine whether an intervention designed to increase mitochondrial biogenesis and dynamics (resveratrol) has favorable effects on our measures of endothelial and mitochondrial function in a randomized, placebo-controlled crossover study in 50 patients with diabetes mellitus. Our proposed studies fit well with the overall theme ofthe Program Project, and we expect to obtain novel information about the contribution of mitochondrial dysfunction to vascular injury that will bring us closer to identifying optimal treatment strategies to reduce cardiovascular risk in diabetes.