Advanced Glycation End-Products in Human Myocardium

人心肌中的高级糖基化终产物

• 批准号: 7474447
• 负责人: MARTIN M LEWINTER
• 金额: $ 65.34万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474447
• 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; Condition; 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; Invasive; Left; Left Ventricular Function; Light; Matrix Metalloproteinase Inhibitor; Measurement; Measures; Mediating; Medical; Methods; Microfilaments; Modeling; Myocardial; Myocardial dysfunction; Myocardium; Nuclear; Numbers; 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; Thinking; Tissues; Ventricular; Vermont; Work; adduct; crosslink; design; glycation; 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）：晚期糖基化最终产物（年龄）是在高血糖和氧化应激等条件下形成的蛋白质加合物。年龄会导致交联，从而改变受影响蛋白的物理特性。在高度易受年龄形成的胶原蛋白中，交联会增加刚度。年龄还通过与年龄（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）的下游变化和MMPS的组织抑制剂（TIMPS）（TIMPS）。多年来，年龄已被认为是糖尿病并发症（DM）并发症的重要贡献。最近，它们与高血压（HTN）和正常衰老有关。在所有这些条件下，胶原蛋白交联被认为是增加血管刚度的重要原因。有很多原因可以假设人心肌存在年龄和相关的胶原蛋白交叉联系，从而导致被动僵硬和舒张功能障碍的增加，但没有解决此问题的数据。该建议是大学之间的合作。佛蒙特州和医疗大学这样。旨在描绘出从手术室中从手术室中解剖的化学皮肤剥离型带有冠状动脉旁路嫁接的患者在手术室中剖析的化学皮肤剥离的化学剥离带中年龄的丰度和功能意义，这些肌肉旁侧心功能良好。在AIM 1中，我们将与DM，HTN和DM+HTN的存在或不存在有关的年龄丰度以及年龄的函数。在AIM 2中，我们将在体外使用年龄交联的断路器Alagebrium来评估交联对被动刚度和肌丝收缩性质的影响，并将这些发现与体内左心室功能联系起来。我们还将使用年龄和年龄信号的临床数据和血浆测量值开发多变量模型，以鉴定心肌年龄增加和相关功能异常的患者。这项工作应该阐明较知的心肌功能障碍机制，这可能在DM，HTN和HTN+DM患者心力衰竭的病理生理学中具有重要意义。降低年龄的药理学方法的持续发展进一步强调了拟议研究的重要性。 项目叙述：晚期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化学上与体内各种蛋白质相连。它们可以通过修饰这些蛋白质的功能来促进疾病。该提案旨在确定晚期糖基化最终产物是否有助于糖尿病和高血压患者的心脏功能障碍以及正常衰老，所有这些都是心力衰竭发展的危险因素。