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。肥胖患者承受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， 血浆化学的有害变化，胰岛素的代偿性过度产生， 胰腺β细胞的最终衰竭和2型糖尿病。因为肥胖患者 同时存在代谢和心血管功能障碍，人们普遍怀疑， 两者是因变量。这在多大程度上是正确的， 代谢和心血管疾病之间的联系尚不清楚。初步数据显示， 应用，我们已经产生了一种新的小鼠模型，其中胰岛素受体 脱敏基因，蛋白酪氨酸磷酸酶1B（PTP1B）从肥胖中缺失 小鼠结果是一只持续肥胖的小鼠和外周胰岛素的校正 阻力肥胖小鼠显示微血管内皮NO介导的 体外血管舒张，通过PTP1B缺失校正的缺陷。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 这些微血管缺陷的潜在机制将在目标1中确定。的 在肥胖小鼠中校正胰岛素抵抗的心血管影响将在 目的2：以血流量、血压和血管重构为终点。而 初步数据提供了新的证据，表明胰岛素抵抗和心血管疾病 功能障碍是联系在一起的，这种关系的性质尚不清楚。高水平的HbA1c 肥胖的小鼠表明环境有利于非酶糖化， 这种联系通过晚期乳腺癌受体表达的增加而得到加强。 糖基化终产物（Glycation End Products，简称GST）。在肥胖PTP1B敲除小鼠中，两种缺陷均得到纠正 改善了胰岛素抵抗这就引出了一个假设， 胰岛素抵抗和心血管功能障碍之间的机械联系， 将在Aim 3中通过产生新的双重KO小鼠、肥胖小鼠和肥胖小鼠来检验假设。 缺少的。总之，这些研究将产生关于 肥胖诱导代谢的机制、介质和生理影响 功能障碍成功地完成这些目标可以确定新的目标，以帮助 治疗肥胖症最常见的临床结果。