Advanced Glycation End-Products in Human Myocardium

人心肌中的高级糖基化终产物

• 批准号: 8133872
• 负责人: MARTIN M LEWINTER
• 金额: $ 64.71万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133872
• 关键词: Address; Advanced Glycosylation End Products; Affect; Age; Animals; Atherosclerosis; Binding; Binding Proteins; 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; Matrix Metalloproteinases; 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; Reaction; Research; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Skin; Tissues; Ventricular; Vermont; Work; adduct; crosslink; design; in vivo; 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.

说明(申请人提供)：晚期糖基化终末产物(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。糖基化终末产物可导致交联，从而改变受影响蛋白质的物理性质。在极易形成老化的胶原蛋白中，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，从而导致核转录因子kappaB(NFKB)介导的促纤维化信号以及基质金属蛋白酶抑制物(MMPs)和基质金属蛋白酶组织抑制物(TIMPs)的下游变化。AGEs多年来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，胶原蛋白的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和相关的胶原交联物存在于人类心肌中，导致被动僵硬和舒张期功能障碍的增加，但没有数据解决这个问题。这项提议是联合国大学之间的一项合作。佛蒙特州和医科大学。当然是这样。AGEs是美国卡罗莱纳州的一项研究，其目的是在化学剥离的试条中描绘AGEs的丰度和功能意义，这些试条是从手术室从左心功能完好的冠状动脉旁路移植患者的心肌活检中分离出来的。在目标1中，我们将量化年龄丰度与DM、HTN和DM+HTN的存在或不存在的关系，并作为年龄的函数。在目标2中，我们将在体外使用AGE交联剂Alagebrium来评估交联剂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功能联系起来。我们还将开发一个多变量模型，使用临床数据和血浆年龄测量以及年龄-RAGE信号来识别心肌年龄增加和相关功能异常的患者。这项工作将有助于揭示一个知之甚少的心肌功能障碍机制，该机制可能在糖尿病、HTN和HTN+DM患者心力衰竭的病理生理学中具有重要意义。减少年龄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。 项目简介：高级糖基化终产物是糖分子的一部分，在氧化应激和炎症条件下，这些糖分子与体内的各种蛋白质发生化学结合。它们可以通过改变这些蛋白质的功能而导致疾病。这项建议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患者以及正常衰老患者的心功能障碍，所有这些都是心力衰竭发展的风险因素。

项目成果

Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy.

• DOI: 10.1152/ajpheart.00063.2014
• 发表时间: 2014-09
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: W. Yarbrough;C. Baicu;R. Mukherjee;An O. Van Laer;William T. Rivers;R. A. McKinney;Corey B Prescott;Robert E. Stroud;Parker D. Freels;Kia N. Zellars;M. Zile;F. Spinale

Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin.

• DOI: 10.1161/circulationaha.114.013215
• 发表时间: 2015-04-07
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Zile MR;Baicu CF;Ikonomidis JS;Stroud RE;Nietert PJ;Bradshaw AD;Slater R;Palmer BM;Van Buren P;Meyer M;Redfield MM;Bull DA;Granzier HL;LeWinter MM
• 通讯作者: LeWinter MM

Zinc-induced cardiomyocyte relaxation in a rat model of hyperglycemia is independent of myosin isoform.

在高血糖大鼠模型中，锌诱导的心肌细胞松弛与肌球蛋白亚型无关。

• DOI: 10.1186/1475-2840-11-135
• 发表时间: 2012
• 期刊: Cardiovascular diabetology
• 影响因子: 9.3
• 作者: Yi,Ting;Cheema,Yaser;Tremble,SarahM;Bell,StephenP;Chen,Zengyi;Subramanian,Meenakumari;LeWinter,MartinM;VanBuren,Peter;Palmer,BradleyM
• 通讯作者: Palmer,BradleyM

Pericardiectomy to Treat Heart Failure With Preserved Ejection Fraction: Unrestrained Enthusiasm?

心包切除术治疗保留射血分数的心力衰竭：无拘无束的热情？

• DOI: 10.1161/circheartfailure.117.003971
• 发表时间: 2017
• 期刊: Circulation. Heart failure
• 作者: LeWinter,MartinM