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Advanced Glycation Endproduct Crosslinking in the Cardiovascular System

Potential Therapeutic Target for Cardiovascular Disease

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Abstract

Advanced glycation endproducts (AGEs) are formed by a reaction between reducing sugars and biological amines. Because of their marked stability, glycated proteins accumulate slowly over a person’s lifespan, and can contribute to age-associated structural and physiological changes in the cardiovascular system such as increased vascular and myocardial stiffness, endothelial dysfunction, altered vascular injury responses and atherosclerotic plaque formation. The mechanisms by which AGEs affect the cardiovascular system include collagen crosslinking, alteration of low-density lipoprotein molecules and impairment of cellular nitric oxide signalling through their interaction with AGE receptors (RAGEs). Thus, the accumulation of AGEs may help to explain the increased cardiac risk associated with aging as well as diabetes mellitus and hypertension, two conditions that accelerate and enhance AGE formation.

A variety of new pharmacological approaches are being developed to reduce the pathophysiological impact of AGEs. These agents can prevent AGE and AGE crosslink formation, break pre-existing AGE crosslinks, and block the interaction between AGEs and RAGEs. Such agents have been shown to reduce vascular and myocardial stiffness, inhibit atherosclerotic plaque formation and improve endothelial function in animal models. Improvement in vascular compliance has also been demonstrated with AGE crosslink breakers in clinical trials. These studies offer promise to reduce the cardiac risk associated with isolated systolic hyperten-sion, diastolic dysfunction and diabetes.

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Acknowledgements

The authors have no potential conflicts of interest to declare. Dr Zieman is an E. Cowles Andrus and a Williams Scholar and is supported by grant funds from the Association of Subspecialty Professors/Society of Geriatric Cardiology and the National Heart Blood and Lung Institute (1K23HL73059-01). Dr Kass is partially supported by a grant from the National Institute on Aging (AG-18324).

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Zieman, S.J., Kass, D.A. Advanced Glycation Endproduct Crosslinking in the Cardiovascular System. Drugs 64, 459–470 (2004). https://doi.org/10.2165/00003495-200464050-00001

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