Modulation of collagen turnover in cardiovascular disease.

Collagen fibers are the most abundant components of the extracellular matrix in arteries and myocardium. Disturbances in the collagen turnover (synthesis and degradation) have been linked to inflammatory diseases including cardiovascular pathological syndromes. In the myocardium, changes in collagen turnover may result in ventricle dilatation and subsequent contractile dysfunction. In arteries, collagen synthesis and degradation are associated with the progression of atherosclerotic disease and intimal hyperplasia following injury. Collagen synthesis is tightly regulated at several levels: synthesis of procollagens, suitable folding of polypeptides, secretion and cross-linking of mature fibers. On the other hand, degradation of newly synthesised procollagen and mature collagen fibers depends on the action of Matrix-Metalloproteinases (MMPs). The major role of collagen turnover in cardiovascular disorders has stimulated the search for pharmacological agents that interfere with collagen turnover at different levels. These drugs can theoretically act through modulation of the synthesis of procollagens or by interference with their post-translational modifications. Another group of pharmacological agents inhibit collagen breakdown (MMP inhibitors). Beneficial effects of compounds that target collagen metabolism have been reported. Unfortunately, many of these compounds also give rise to serious adverse effects due to interference with vital biological processes in which collagen plays an important role. In this paper, we will review cardiovascular diseases in which altered local collagen turnover is a key feature. Subsequently, the effect of compounds that have been developed and tested to modulate collagen synthesis, cross-linking or breakdown will be discussed.