Metabolic Determinants of Cardiovascular Dysfunction in Obesity

项目摘要 心血管疾病继发的发病率和死亡率是主要的健康问题 在肥胖患者身上。肥胖患者背负着一系列代谢功能障碍的负担 与超重有关。其中最值得注意的是胰岛素抵抗，它会导致 血浆化学的有害变化，代偿性胰岛素过量和 胰岛β细胞的最终衰竭和2型糖尿病。因为肥胖患者 目前存在代谢和心血管功能障碍，人们普遍怀疑 这两者是因变量。这在多大程度上是真实的，以及机制 代谢性疾病和心血管疾病之间的联系尚不清楚。在这方面的初步数据中 应用，我们已经建立了一种新的小鼠模型，在该模型中，胰岛素受体 肥胖患者脱敏基因蛋白酪氨酸磷酸酶1B缺失 老鼠。结果是一只小鼠持续肥胖并纠正了外周胰岛素 抵抗。肥胖小鼠表现出NO介导的微血管内皮损伤 体外血管扩张，通过PTP1B缺失纠正的缺陷。这表明胰岛素 抵抗力是肥胖引起的代谢功能障碍的原因。分子 这些微血管缺陷的机制将在目标1中确定。 纠正肥胖小鼠胰岛素抵抗对心血管的影响将在 目的2，以血流、血压和血管重塑为终点。而当 初步数据提供了新的证据表明胰岛素抵抗和心血管疾病 功能障碍是有联系的，这种关系的性质尚不清楚。体内HbA1c水平较高 肥胖的小鼠暗示了一种有利于非酶糖化的环境，而这 高级受体的表达增加加强了关联性 糖基化终产物(RAGE)。在肥胖的PTP1B缺失小鼠中，这两种缺陷都得到了纠正 改善了胰岛素抵抗。这就引出了一种假设，即愤怒是 胰岛素抵抗和心血管功能障碍之间的机制联系 在目标3中，将通过产生新的双重KO小鼠--肥胖小鼠来检验这一假设 缺乏愤怒。总而言之，这些研究将产生关于 肥胖诱导代谢的机制、调节因素及生理影响 功能障碍。成功完成这些目标可能会确定新的目标，以帮助 治疗肥胖症最常见的临床结局。

Project Abstract Morbidity and mortality secondary to cardiovascular disease is the major health problem in obese patients. Obese patients are burdened with an array of metabolic dysfunctions associated with excess weight. Most notable of these is insulin resistance which causes deleterious changes in plasma chemistry, compensatory over-production of insulin and eventual failure of the pancreatic beta-cell and Type 2 diabetes. Because obese patients present with both metabolic and cardiovascular dysfunction, it is widely suspected that the two are dependent variables. The extent to which this is true and the mechanisms linking metabolic and cardiovascular disease are unknown. In preliminary data for this application, we have generated a novel mouse model in which an insulin receptor desensitizing gene, protein tyrosine phosphatase 1B (PTP1B) is deleted from obese mice. The result is a mouse with persistent obesity and correction of peripheral insulin resistance. Obese mice show impairment of microvascular endothelial NO-mediated vasodilation in vitro, a defect corrected by PTP1B deletion. This suggests that insulin resistance is the causal aspect of obesity-induced metabolic dysfunction. The molecular mechanisms underlying these microvascular defects will be determined in Aim 1. The cardiovascular impact of correcting insulin resistance in obese mice will be determined in Aim 2, using blood flow, blood pressure and vascular remodeling as endpoints. While preliminary data provides novel evidence that insulin resistance and cardiovascular dysfunction are linked, the nature of this relationship is unclear. High levels of HbA1c in obese mice suggest an environment favorable to non-enzymatic glycation and this association is strengthened by the increased expression of the Receptor for Advanced Glycation End-products (RAGE). Both deficits are corrected in obese PTP1B null mice with improved insulin resistance. This leads us to the hypothesis that RAGE is the mechanistic link between insulin resistance and cardiovascular dysfunction and this hypothesis will be tested in Aim 3 by the generation of novel dual KO mice, obese mice lacking RAGE. Taken together, these studies will generate new information about the mechanisms, mediators and physiologic impact of obesity-induced metabolic dysfunction. Successful completion of these aims may identify new targets to aid in the treatment of the most common clinical outcomes of obesity.