Cross-link breakers as a new therapeutic approach to cardiovascular disease

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Abstract
Fibrillar proteins, such as collagens type I and III, and elastin are components of the extracellular matrix. They form an intricate widespread network that provides a basis for maintaining the physical structure of the heart and vessels and also play an important role in determining cardiovascular function. Physiologically, collagen and elastin fibres are enzymatically cross-linked to form matrix. In addition to these enzymatically formed cross-links, collagen fibres may be linked non-enzymatically, most notably by formation of AGEs (advanced glycation end-products). AGEs are formed by a reaction between reducing sugars and body proteins; they are formed increasingly in diabetes mellitus and hypertension and they accumulate with aging. There are several mechanisms whereby AGEs may affect cardiovascular structure and function. These include increased myocardial and vascular stiffness and (upon reaction with their receptors) inflammatory reactions, release of growth factors and cytokines, and increased oxidative stress. Therefore breaking AGEs appears as a promising tool in the therapy of cardiovascular injury related to diabetes, hypertension and aging. Breakers of AGE cross-links have been developed and one of them, alagebrium, has been extensively studied. This brief review discusses the formation of AGEs, their role in mediating cardiovascular injury, as well as the results of experimental and clinical studies involving alagebrium.