Matrix metalloproteinases in the pathology of natural and bioprosthetic cardiac valves

Abstract

Degenerative dysfunction of cardiac valves may be accounted for by uncontrolled extracellular matrix degradation processes in which matrix metalloproteinases could play a major role. In this study, 24 pathologic human valves and 26 pericardial-derived bioprostheses were analysed for metalloproteinases by gelatin zymography. Compared to controls, human stenotic valves and bioprostheses explanted because of either calcifying or noncalcifying degeneration revealed three notable biochemical aspects: (1) an amplification in the levels of metalloproteinase 9 (gelatinase B), suggestive of its active role in valvular pathology; (2) minimal modifications in the gelatinolytic levels of metalloproteinase 2 (gelatinase A), indicative of a constitutive secretion; and (3) activation products derived from both gelatinase A and B. All gelatinolytic activities identified in pathologic specimens were inhibited in vitro by zinc and calcium chelators (captopril, doxycycline, dithiothreitol, and ethylenediaminotetraacetic acid), suggesting potential therapeutic approaches. High levels of beta-glucuronidase (a lysosomal marker enzyme for phagocytic cells) were found in human calcified stenotic valves and in ruptured and calcified pericardial-derived bioprostheses. Mononuclear recruitment was minimal to moderate in pathologic human valves, and in noncalcified ruptured bioprostheses infiltrating mononuclear cells were concentrated in large numbers at the cuspal free edge. These findings suggest the involvement of infiltrating phagocytic cells and putative common mechanisms in the degeneration of both the natural and the bioprosthetic valvular extracellular matrix (ECM).