Coronary Dysregulation Associated with Obesity

描述(由申请人提供)： 糖尿病和肥胖症在退伍军人管理局医疗系统照顾的患者群体中以及在普通人群中已经达到流行水平。肥胖会增加患高血压、中风、高胆固醇血症、心脏病和II型糖尿病的风险。肥胖的心血管疾病的前奏是血管功能障碍的发展。然而，将肥胖与血管并发症联系起来的病理机制还不是很清楚。为了预防与糖尿病和肥胖症的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是很重要的。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。降钙素基因相关肽从神经末梢直接释放到血管平滑肌上，诱导血管扩张。我们发现，CGRP介导的扩张在高脂饮食大鼠的冠状动脉和糖尿病大鼠的肾动脉中被减弱。CGRP反应改变的机制尚不清楚。我们相信，提高我们对这种肽在正常和疾病模型中对血管功能的作用的理解，可以为2型糖尿病和肥胖症患者群体的血管疾病带来创新的治疗方法。需要检验的假设是，与2型糖尿病和肥胖症相关的对CGRP的异常血管反应是由于支配血管的感觉神经中CGRP含量减少，以及CGRP降解、CGRP受体成分表达和/或由CGRP激活的细胞内信号机制的变化。我们的具体目标包括：1.确定饮食诱导的肥胖合并和不合并2型糖尿病对血管中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/或活性的变化导致CGRP的降解；b)CGRP受体组分的表达改变；c)CGRP受体激活后下游信号通路的激活改变，如腺苷环化酶、PKA或K+通道。拟议的研究将使用肥胖抵抗(OR)和肥胖倾向(OP)大鼠，无论是否有高血糖。或者老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、肠系膜和肾动脉的血管反应性。代谢参数和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导致的血管功能障碍的机制，并开发能够预防或扭转不利心血管后果的治疗方法。随着全球II型糖尿病的增加和年轻人群中肥胖发病的增加，向这些人提供卫生保健的负担将继续增加。 公共卫生相关性： 糖尿病和肥胖已经达到流行水平，并增加了高血压、中风、高胆固醇血症和心脏病的风险。与糖尿病和肥胖症相关的医疗成本继续大幅增加。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善这些患者预防或治疗心脏病的护理标准非常重要。我们认为，提高我们对降钙素基因相关肽(CGRP)在糖尿病和肥胖症相关血管功能障碍中的作用的理解，可能会导致这些患者群体的创新治疗。

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.