Advanced Glycation End-Products in Human Myocardium

描述（由申请人提供）：晚期糖基化终产物（AGEs）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。AGEs会导致交联，从而改变受影响蛋白质的物理性质。胶原蛋白极易形成AGE，交联会增加硬度。AGEs还通过与AGEs受体（RAGE）相互作用增加胶原含量，从而导致通过核转录因子κ B （NFKB）介导的促纤维化信号和基质金属蛋白酶抑制剂（MMPs）和MMPs的组织抑制剂（TIMPS）的下游变化。多年来，AGEs一直被认为是糖尿病（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增加的重要原因。有许多理由可以假设AGEs和相关的胶原交联存在于人类心肌中，导致被动僵硬和舒张功能障碍增加，但没有数据解决这一问题。这项提案是佛蒙特大学和加州医科大学的合作。该研究旨在描述在手术室内从冠脉搭桥术患者的左心室功能保存良好的心肌活组织切片中剥离的化学剥皮条中AGEs的丰度和功能意义。在目标1中，我们将量化与DM、HTN和DM+HTN存在与否相关的AGE丰度，并将其作为年龄的函数。在Aim 2中，我们将使用AGE交联抑制剂Alagebrium在体外评估交联对被动僵硬和肌丝收缩特性的影响，并将这些发现与体内左心室功能联系起来。我们还将开发一个多变量模型，利用临床数据和血浆AGEs和AGE-RAGE信号测量来识别心肌AGEs升高和相关功能异常的患者。这项工作将揭示一个尚不清楚的心肌功能障碍机制，这可能对糖尿病、HTN和HTN+DM患者心力衰竭的病理生理具有重要意义。正在进行的减少AGEs的药理学方法的发展进一步强调了所提出的研究的重要性。

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.