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.

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糖加合物。AGEs可导致交联，从而改变受影响蛋白质的物理性质。在胶原蛋白中，它对AGE的形成非常敏感，交联增加了硬度。AGEs还通过与AGEs的受体（AGEs）相互作用增加胶原蛋白含量，这导致通过核转录因子κ B（NF κ B）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（TIMP）的下游变化。AGEs是糖尿病（DM）并发症的一个重要因素。最近，它们与高血压（HTN）和正常衰老有关。在所有这些条件下，胶原交联被认为是血管硬度增加的重要原因。有许多理由假设AGEs和相关的胶原交联存在于人类心肌中，导致被动僵硬增加和舒张功能障碍，但没有数据解决这个问题。该提案是佛蒙特大学和So医科大学之间的合作。卡罗莱纳，其目的是描绘从手术室获得的接受冠状动脉旁路移植术的左心室功能保存良好的患者的心肌活检中解剖的化学皮肤条中AGEs的丰度和功能意义。在目标1中，我们将量化AGE丰度与DM、HTN和DM+HTN的存在或不存在的关系以及作为年龄的函数。在目标2中，我们将在体外使用AGE交联破坏剂Alagelis来评估交联对被动刚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联系起来。我们还将开发一个多变量模型，采用临床数据和AGEs和AGE-binding信号的血浆测量来识别心肌AGEs增加和相关功能异常的患者。这项工作应该阐明一个不太清楚的心肌功能障碍的机制，可能是具有重大意义的糖尿病，高血压和高血压+糖尿病患者的心力衰竭的病理生理学。减少AGEs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与体内的各种蛋白质化学连接。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产物是否会导致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