Coronary Dysregulation Associated with Obesity

与肥胖相关的冠状动脉失调

• 批准号: 8397586
• 负责人: Christine L OLTMAN
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397586
• 关键词: Acetylcholine; Adenosine; Adenylate Cyclase; American Heart Association; Arteries; Attenuated; Blood Vessels; C-Type Natriuretic Peptide; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cardiovascular Diseases; Cardiovascular system; Caring; Complex; Coronary; Coronary Circulation; Coronary artery; Coronary heart disease; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Diet; Dilator; Disease; Disease model; Epidemic; Evaluation; Fatty acid glycerol esters; Functional disorder; General Population; Goals; Health Care Costs; Healthcare; Heart Diseases; Hyperglycemia; Hypertension; Incidence; Individual; Innovative Therapy; Kidney Diseases; Lead; Link; Mediating; Medical; Mesenteric Arteries; Metabolic; Neprilysin; Nerve; Nerve Endings; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Pathology; Patients; Peptides; Peripheral Nervous System; Physiological; Population; Potassium Channel; Prevalence; Property; Rattus; Receptor Activation; Relaxation; Renal Circulation; Research; Resistance; Risk; Risk Factors; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Stroke; Substance P; System; Testing; United States Department of Veterans Affairs; Vascular Diseases; Vascular Smooth Muscle; Vasodilation; Vasodilator Agents; Work; afferent nerve; diabetic rat; disorder risk; feeding; hypercholesterolemia; improved; patient population; prevent; public health relevance; receptor; renal artery; response; second messenger; standard of care; therapeutic target; therapy development; vasoactive agent

DESCRIPTION (provided by applicant): Diabetes and obesity has reached epidemic levels in the patient population cared for by the Veterans Administration Medical System as well as in the general population. Obesity increases the risk for hypertension, stroke, hypercholesterolemia, heart disease, and type II diabetes. A prelude to cardiovascular disease in obesity is development of vascular dysfunction. However, the pathology linking obesity to vascular complications is not well known. In order to prevent complications associated with cardiovascular dysfunction in diabetes and obesity, it is important to improve our understanding of underlying mechanisms. Calcitonin gene-related peptide (CGRP) is a very potent physiological microvascular dilator. CGRP is released from nerve endings directly onto vascular smooth muscle to induce vasodilation. We have found that CGRP mediated dilation is attenuated in coronary arteries from high fat fed rats and in renal arteries from diabetic rats. The mechanisms involved in altered CGRP responses are not known. We believe that improving our understanding of the role of this peptide on vascular function both normal and disease models could lead to innovative therapies for vascular disease in patient populations with type 2 diabetes and obesity. The hypothesis to be tested is that abnormal vascular responses to CGRP associated with type 2 diabetes and obesity are due to decreased CGRP content in sensory nerves innervating the vasculature and alterations in degradation of CGRP, expression of CGRP receptor components and/or intracellular signaling mechanisms activated by CGRP. Our specific objectives include: 1. Determine the effect of diet induced obesity with and without type 2 diabetes on CGRP levels in the vasculature and CGRP vascular reactivity. 2. Determine mechanisms involved in vascular dysfunction associated with type 2 diabetes and obesity, including a) degradation of CGRP due to changes in expression and/or activity of NEP b) altered expression of CGRP receptor components c) alterations in activation of downstream signaling pathways following CGRP receptor activation, such as adenylate cyclase, PKA, or K+ channels. The proposed studies will use obesity resistant (OR) and obesity prone (OP) rats with and without hyperglycemia. OR rats will allow evaluation of diet on vascular reactivity. We will examine vascular reactivity in coronary, mesenteric and renal arteries. Metabolic parameters and expression of CGRP receptor components and NEP will also be determined. There is a pressing need to identify mechanisms of vascular dysfunction attributed to diabetes and obesity and to develop therapies that can prevent or reverse adverse cardiovascular consequences. With the global increase in type II diabetes and onset of obesity increasing in younger populations, the burden to deliver health care to these individuals will continue to increase.

描述（由申请人提供）： 在退伍军人管理系统以及普通人群中，糖尿病和肥胖症已经达到了患者人群的流行水平。肥胖增加了高血压，中风，高胆固醇血症，心脏病和II型糖尿病的风险。肥胖症中心血管疾病的前奏是血管功能障碍的发展。但是，将肥胖与血管并发症联系起来的病理尚不清楚。为了防止糖尿病和肥胖症中与心血管功能障碍有关的并发症，提高我们对基本机制的理解非常重要。 降钙素基因相关肽（CGRP）是一种非常有效的生理微血管扩张剂。 CGRP从神经末端直接释放到血管平滑肌上，以诱导血管舒张。我们发现，来自高脂喂养大鼠和糖尿病大鼠的肾动脉中的CGRP介导的扩张会减弱。 CGRP响应改变的机制尚不清楚。我们认为，提高对这种肽在血管功能的作用正常和疾病模型的理解可能会导致2型糖尿病和肥胖症患者血管疾病的创新疗法。 要检验的假设是，与2型糖尿病和肥胖相关的对CGRP的异常血管反应是由于CGRP含量降低了感官神经中的CGRP含量，导致CGRP的脉管神经和CGRP降解的改变，CGRP受体成分的表达以及CGRP激活CGRP的CGRP受体成分的表达和/或或/或或/或或/或或/或或/或或或或或含量。我们的具体目标包括：1。确定饮食诱导的肥胖症的影响有或没有2型糖尿病对血管和CGRP血管反应性中CGRP水平的影响。 2。确定与2型糖尿病和肥胖相关的血管功能障碍的机制，包括a）由于NEP的表达和/或活性的变化，CGRP受体成分的表达变化而导致CGRP降解，CGRP受体成分的表达改变了CGRP受体激活途径激活的CGRP受体成分的变化，而CGRP受体激活途径的激活变化，例如。 拟议的研究将使用有或没有高血糖的耐心（OR）和肥胖症（OP）大鼠。或大鼠将允许评估血管反应性的饮食。我们将检查冠状动脉，肠系膜和肾动脉的血管反应性。还将确定CGRP受体成分和NEP的代谢参数和表达。 需要确定归因于糖尿病和肥胖的血管功能障碍的机制，并开发可预防或逆转不良心血管后果的疗法。随着II型糖尿病的全球增长和肥胖症的发作，年轻人的糖尿病开始增加，为这些人提供医疗保健的负担将继续增加。