Coronary Dysregulation Associated with Obesity

与肥胖相关的冠状动脉失调

• 批准号: 8262641
• 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/8262641
• 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; 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. PUBLIC HEALTH RELEVANCE: Diabetes and obesity have reached epidemic levels, and increases the risk for hypertension, stroke, hypercholesterolemia, and heart disease. Health costs associated with diabetes and obesity continue to increase dramatically. Understanding mechanisms involved in cardiovascular dysfunction associated with development of diabetes and obesity is important for determining an improved standard of care to prevent or treat heart disease in these patients. We propose that improving our understanding of the role of calcitonin gene related peptide (CGRP) in vascular dysfunction associated with diabetes and obesity may lead to innovative therapies in these patient populations.

描述（由申请人提供）： 在退伍军人管理局医疗系统照顾的患者群体以及普通人群中，糖尿病和肥胖症已达到流行水平。肥胖会增加患高血压、中风、高胆固醇血症、心脏病和二型糖尿病的风险。肥胖引起的心血管疾病的前奏是血管功能障碍的发生。然而，肥胖与血管并发症之间的病理联系尚不清楚。为了预防与糖尿病和肥胖症心血管功能障碍相关的并发症，提高我们对潜在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性微血管扩张剂。 CGRP从神经末梢直接释放到血管平滑肌上以诱导血管舒张。我们发现，在高脂肪喂养的大鼠的冠状动脉和糖尿病大鼠的肾动脉中，CGRP 介导的扩张减弱。 CGRP 反应改变所涉及的机制尚不清楚。我们相信，加深对这种肽对正常和疾病模型血管功能的作用的了解，可能会为患有 2 型糖尿病和肥胖症的患者群体带来血管疾病的创新疗法。 待检验的假设是，与 2 型糖尿病和肥胖相关的血管对 CGRP 的异常反应是由于支配脉管系统的感觉神经中 CGRP 含量减少以及 CGRP 降解、CGRP 受体成分表达和/或细胞内信号机制激活的改变所致。由CGRP。我们的具体目标包括： 1. 确定饮食诱发的肥胖（伴或不伴 2 型糖尿病）对脉管系统中 CGRP 水平和 CGRP 血管反应性的影响。 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 表达和/或活性变化而导致 CGRP 降解 b) CGRP 受体成分表达改变 c) 下游信号通路激活的改变CGRP 受体激活后，例如腺苷酸环化酶、PKA 或 K+ 通道。 拟议的研究将使用患有或不患有高血糖的抗肥胖（OR）和易肥胖（OP）大鼠。 OR 大鼠将允许评估饮食对血管反应性的影响。我们将检查冠状动脉、肠系膜动脉和肾动脉的血管反应性。代谢参数以及 CGRP 受体成分和 NEP 的表达也将被确定。 迫切需要确定糖尿病和肥胖引起的血管功能障碍的机制，并开发可以预防或逆转不良心血管后果的疗法。随着全球二型糖尿病的增加和年轻人群中肥胖症发病率的增加，为这些人提供医疗保健的负担将继续增加。 公共卫生相关性： 糖尿病和肥胖已达到流行水平，并增加了高血压、中风、高胆固醇血症和心脏病的风险。与糖尿病和肥胖相关的健康成本继续急剧增加。了解与糖尿病和肥胖症发展相关的心血管功能障碍的机制对于确定改进的护理标准以预防或治疗这些患者的心脏病非常重要。我们建议，提高对降钙素基因相关肽（CGRP）在与糖尿病和肥胖相关的血管功能障碍中的作用的理解可能会为这些患者群体带来创新疗法。