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 发病率和死亡率继发于心血管疾病是主要的健康问题 在肥胖的患者中。肥胖患者有一系列代谢功能障碍负担 与体重过大有关。其中最值得注意的是胰岛素抵抗 血浆化学的有害变化，胰岛素和 胰腺β细胞和2型糖尿病的最终失败。因为肥胖的患者 存在代谢和心血管功能障碍，人们普遍怀疑 这两个是因变量。这是真实的程度和机制 连接代谢和心血管疾病是未知的。在此初步数据中 应用，我们生成了一种新型的小鼠模型，其中胰岛素受体 脱敏基因，蛋白酪氨酸磷酸酶1B（PTP1B）被从肥胖中删除 老鼠。结果是一只具有持续肥胖症和外周胰岛素校正的小鼠 反抗。肥胖小鼠显示微血管内皮无介导的损害 在体外血管舒张，通过PTP1B缺失纠正的缺陷。这表明胰岛素 抗性是肥胖引起的代谢功能障碍的因果方面。分子 这些微血管缺陷的基础机制将在AIM 1中确定。 将在肥胖小鼠中校正胰岛素抵抗的心血管影响。 AIM 2，使用血流，血压和血管重塑作为终点。尽管 初步数据提供了胰岛素抵抗和心血管的新证据 功能障碍是连接的，这种关系的性质尚不清楚。高水平的HBA1C 肥胖的小鼠提出了一个有利于非酶糖化的环境，这是 通过增加的高级表达来增强关联 糖基化终产（RAGE）。两种缺陷均在肥胖的PTP1B无效小鼠中纠正 具有改善的胰岛素抵抗。这使我们提出了一个假设，即愤怒是 胰岛素抵抗与心血管功能障碍之间的机械联系，这 假设将通过新颖的双KO小鼠（肥胖小鼠）的产生在AIM 3中检验 缺乏愤怒。综上所述，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。这些目标的成功完成可能会确定新目标以帮助 治疗肥胖的最常见临床结果。