Metabolic Determinants of Cardiovascular Dysfunction in Obesity

肥胖引起的心血管功能障碍的代谢决定因素

• 批准号: 8197672
• 负责人: David J Fulton
• 金额: $ 42.79万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197672
• 关键词: Accounting; Advanced Glycosylation End Products; Affect; American; Animals; Blood Pressure; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Chemistry; Clinical; Data; Defect; Endothelium; Environment; Enzymes; Epidemic; Failure; Functional disorder; Gene Proteins; Generations; Glucose; Glucose Intolerance; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Health; Hepatic; Human; Hyperglycemia; Hyperinsulinism; Hypertrophy; Impairment; In Vitro; Individual; Insulin; Insulin Receptor; Insulin Resistance; Knockout Mice; Leptin; Link; Lipids; Liver; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic syndrome; Microcirculation; Molecular; Morbidity - disease rate; Mus; Muscle; NADPH Oxidase; Nature; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome; Oxidants; Pathway interactions; Patients; Peripheral; Physiological; Plasma; Production; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Secondary to; Structure of beta Cell of islet; Superoxides; Testing; Tissues; Up-Regulation; Vascular Proliferation; Vascular Smooth Muscle; Vascular remodeling; Vasodilation; Weight; abstracting; blood pressure regulation; cardiovascular risk factor; cell type; db/db mouse; glycation; glycemic control; improved; in vivo; indexing; insulin sensitivity; insulin signaling; mortality; mouse model; new therapeutic target; novel; protein tyrosine phosphatase 1B; receptor; receptor expression; receptor for advanced glycation endproducts; research study

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.

项目摘要 继发于心血管疾病的发病率和死亡率是主要的健康问题 在肥胖患者中。肥胖患者患有一系列代谢功能障碍 与体重过重有关。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、胰岛素的代偿性过量产生和 胰腺β细胞最终衰竭和2型糖尿病。因为肥胖患者 存在代谢和心血管功能障碍，人们普遍怀疑 两者是因变量。这在多大程度上属实以及机制 代谢与心血管疾病之间的联系尚不清楚。在这方面的初步数据中 应用程序中，我们生成了一种新型小鼠模型，其中胰岛素受体 肥胖者删除了脱敏基因，蛋白酪氨酸磷酸酶 1B (PTP1B) 老鼠。结果是一只持续肥胖的小鼠和外周胰岛素的校正 反抗。肥胖小鼠显示 NO 介导的微血管内皮损伤 体外血管舒张，这是通过 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 这些微血管缺陷背后的机制将在目标 1 中确定。 纠正肥胖小鼠胰岛素抵抗对心血管的影响将在 目标 2，使用血流量、血压和血管重塑作为终点。尽管 初步数据提供了新的证据，表明胰岛素抵抗和心血管疾病 功能障碍之间存在联系，但这种关系的性质尚不清楚。 HbA1c 水平较高 肥胖小鼠表明有利于非酶糖化的环境，这 高级受体表达的增加增强了关联性 糖化终产物（RAGE）。这两种缺陷在肥胖 PTP1B 缺失小鼠中均得到纠正 并改善胰岛素抵抗。这使我们得出这样的假设：RAGE 是 胰岛素抵抗与心血管功能障碍之间的机制联系 假设将在目标 3 中通过生成新型双 KO 小鼠、肥胖小鼠进行检验 缺乏愤怒。总而言之，这些研究将产生有关 肥胖引起的代谢的机制、介质和生理影响 功能障碍。成功完成这些目标可能会确定新的目标来帮助 治疗肥胖最常见的临床结果。