Advanced Glycation End-Products in Human Myocardium

人心肌中的高级糖基化终产物

• 批准号: 7923815
• 负责人: MARTIN M LEWINTER
• 金额: $ 65.36万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923815
• 关键词: Address; Advanced Glycosylation End Products; Affect; Age; Animals; Atherosclerosis; Binding; Binding Proteins; Biochemical Reaction; Biopsy; Blood Vessels; Clinical; Clinical Data; Collaborations; Collagen; Complex; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Coronary Artery Bypass; DNA Sequence Rearrangement; Data; Development; Diabetes Mellitus; Disease; EFRAC; Fibrosis; Frequencies; Functional disorder; Glucose; Goals; Heart; Heart Diseases; Heart failure; Human; Hyperglycemia; Hypertension; In Vitro; Inflammation; Inflammatory; Left; Left Ventricular Function; Light; Matrix Metalloproteinase Inhibitor; Measurement; Measures; Mediating; Medical; Methods; Microfilaments; Modeling; Myocardial; Myocardial dysfunction; Myocardium; Nuclear; Operating Rooms; Output; Oxidative Stress; Pathogenesis; Patients; Performance; Plasma; Prevalence; Production; Property; Proteins; Research Project Grants; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Skin; Tissues; Ventricular; Vermont; Work; adduct; crosslink; design; in vivo; inhibitor/antagonist; normal aging; physical property; protein function; receptor; receptor for advanced glycation endproducts; sugar; transcription factor

DESCRIPTION (provided by applicant): Advanced glycation end-products (AGEs) are sugar adducts to proteins that form under conditions such as hyperglycemia and oxidative stress. AGEs can result in cross-linking that alters the physical properties of affected proteins. In collagen, which is highly susceptible to AGE formation, cross-linking increases stiffness. AGEs also increase collagen content by interacting with the receptor for AGEs (RAGE), which results in pro-fibrotic signaling mediated via nuclear transcription factor kappa B (NFKB) and downstream changes in matrix metalloproteinase inhibitors (MMPs) and tissue inhibitors of MMPs (TIMPS). AGEs have been recognized for many years as an important contributor to the complications of diabetes mellitus (DM). More recently, they have been implicated in hypertension (HTN) and normal aging. In all of these conditions, collagen- crosslinking is thought to be an important cause of increased vascular stiffness. There are a number of reasons to hypothesize that AGEs and associated collagen cross- linking are present in human myocardium, resulting in increased passive stiffness and diastolic dysfunction, but there are no data addressing this issue. This proposal is a collaboration between the Univ. of Vermont and the Medical Univ. of So. Carolina that is designed to delineate the abundance and functional significance of AGEs in chemically skinned strips dissected from myocardial biopsies obtained in the Operating Room from patients undergoing coronary bypass grafting who have well-preserved left ventricular function. In Aim 1 we will quantify AGE abundance in relation to the presence or absence of DM, HTN and DM+HTN and as a function of age. In Aim 2 we will use the AGE cross-link breaker Alagebrium in vitro to assess effects of cross-links on both passive stiffness and myofilament contractile properties and relate these findings to in vivo left ventricular function. We will also develop a multi-variate model employing clinical data and plasma measurements of AGEs and AGE-RAGE signaling to identify patients with increased myocardial AGEs and associated functional abnormalities. This work should shed light on a poorly understood mechanism of myocardial dysfunction that may be of major significance in the pathophysiology of heart failure in patients with DM, HTN and HTN+DM. The ongoing development of pharmacologic approaches to reduce AGEs further underscores the importance of the proposed research. Project Narrative: Advanced glycation end-products are portions of sugar molecules that become chemically attached to various proteins in the body under conditions of oxidative stress and inflammation. They can contribute to disease by modifying the function of these proteins. This proposal seeks to determine whether advanced glycation end-products contribute to heart dysfunction in patients with diabetes mellitus and hypertension as well as normal aging, all of which are risk factors for the development of heart failure.

描述（由申请人提供）：晚期糖基化终产物（AGE）是在高血糖和氧化应激等条件下形成的蛋白质的糖加合物。 AGE 会导致交联，从而改变受影响蛋白质的物理特性。在对 AGE 形成高度敏感的胶原蛋白中，交联会增加硬度。 AGE 还通过与 AGE 受体 (RAGE) 相互作用来增加胶原蛋白含量，从而导致通过核转录因子 kappa B (NFKB) 介导的促纤维化信号传导以及基质金属蛋白酶抑制剂 (MMP) 和 MMP 组织抑制剂 (TIMPS) 的下游变化）。多年来，AGE 一直被认为是导致糖尿病 (DM) 并发症的重要因素。最近，它们与高血压（HTN）和正常衰老有关。在所有这些情况下，胶原交联被认为是血管僵硬度增加的重要原因。有多种理由可以推测人类心肌中存在 AGE 和相关的胶原交联，导致被动僵硬度增加和舒张功能障碍，但没有数据解决这个问题。该提案是大学之间的合作。佛蒙特州和医科大学。所以。 Carolina 旨在描述从手术室获得的左心室功能保存良好的冠状动脉旁路移植患者的心肌活检中解剖的化学剥皮条中 AGE 的丰度和功能意义。在目标 1 中，我们将量化与 DM、HTN 和 DM+HTN 是否存在相关的 AGE 丰度，并作为年龄的函数。在目标 2 中，我们将在体外使用 AGE 交联破坏剂 Alagebrium 来评估交联对被动硬度和肌丝收缩特性的影响，并将这些发现与体内左心室功能相关联。我们还将开发一个多变量模型，利用临床数据和 AGE 和 AGE-RAGE 信号传导的血浆测量值来识别心肌 AGE 增加和相关功能异常的患者。这项工作应该揭示人们知之甚少的心肌功能障碍机制，这可能对 DM、HTN 和 HTN+DM 患者心力衰竭的病理生理学具有重要意义。减少 AGE 的药理学方法的不断发展进一步强调了拟议研究的重要性。 项目叙述：高级糖基化终产物是糖分子的一部分，在氧化应激和炎症的条件下，以化学方式附着在体内的各种蛋白质上。它们可以通过改变这些蛋白质的功能而导致疾病。该提案旨在确定晚期糖基化终末产物是否会导致糖尿病和高血压以及正常衰老患者的心功能障碍，所有这些都是发生心力衰竭的危险因素。