Advanced Glycation End-Products in Human Myocardium

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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.