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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

基本信息

批准号：
8383466
负责人：
David J Fulton
金额：
$ 39.81万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8383466
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

项目摘要

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。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increasing muscle mass improves vascular function in obese (db/db) mice.

DOI：
10.1161/jaha.114.000854
发表时间：
2014-06-25
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Qiu S;Mintz JD;Salet CD;Han W;Giannis A;Chen F;Yu Y;Su Y;Fulton DJ;Stepp DW
通讯作者：
Stepp DW

The subcellular compartmentalization of arginine metabolizing enzymes and their role in endothelial dysfunction.

DOI：
10.3389/fimmu.2013.00184
发表时间：
2013
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Chen F;Lucas R;Fulton D
通讯作者：
Fulton D

Endothelial PFKFB3 plays a critical role in angiogenesis.

内皮PFKFB3在血管生成中起关键作用。

DOI：
10.1161/atvbaha.113.303041
发表时间：
2014-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Xu Y;An X;Guo X;Habtetsion TG;Wang Y;Xu X;Kandala S;Li Q;Li H;Zhang C;Caldwell RB;Fulton DJ;Su Y;Hoda MN;Zhou G;Wu C;Huo Y
通讯作者：
Huo Y

Increased epidermal growth factor-like ligands are associated with elevated vascular nicotinamide adenine dinucleotide phosphate oxidase in a primate model of atherosclerosis.