Cathepsin K: boon or bale for atherosclerotic plaquestability?

摘要

Cathepsins, cysteine proteases of lysosomes and endosomes, play major physiological roles in general intracellular protein turnover. When they are directed outside the cell, these enzymes also take part in remodelling the extracellular matrix of bone1 and other tissues. Once in the extracellular matrix, the cathepsins degrade elastin and collagen. Since remodelling of the extracellular matrix of arteries is germane to the stabilization of established atherosclerotic plaques, considerable interest is being focused on cathepsins as possible therapeutic targets for plaque stabilization. Undesirable as they may be, atherosclerotic plaques, once formed, have to be maintained in a stable condition to avoid rupture of their collagenous fibrotic cap and the ensuing occlusion of critical cardiac vessels or arteries of the brain and, hence, coronary artery disease or stroke. Plaques with high collagen levels are more stable than plaques containing lower amounts of this matrix protein. Thus, increasing the collagen content of the plaque supports plaque stability, and modulation of plaque collagen content by manipulating the cathepsins with inhibitors potentially constitutes a means by which the stability of the existing plaques might be controlled therapeutically. Cathepsins B, F, L, K, and S are indeed expressed in plaques, suggesting involvement of these enzymes in degrading plaque collagen and implicating that the cathepsins exert a baleful effect on plaque stability.2 Ironically, the collagen content in atherosclerotic plaques of ApoE~-/- mice deficient in cystatin C, a natural inhibitor of the cathepsins, was not reduced, as would be expected after deletion of the cathepsin inhibitor, but increased,3 seemingly a boon for plaque stability. These contradictory findings indicate how the influence of cathepsins on plaque integrity during atherogenesis is more complicated than initially meets the eye#