Digesting the Remodeled Heart

Abstract

Of the many proteinases present in the myocardium, members of the matrix metalloproteinase (MMP) family have received most attention. However, the cysteine proteases and their inhibitors have now been implicated in the pathogenesis of cardiac remodeling in the hypertrophied and failing heart. Cathepsins, cysteine proteases of the papain family, are optimally active in the acidic pH of lysosomes and are responsible for the physiological digestive turnover of cellular molecules and organelles. We now know that the levels of cathepsins and their endogenous inhibitors, cystatins, can be regulated by a number of signaling molecules, and cathepsins can be released from lysosomes into the extracellular space. Cysteine proteinases may degrade extracellular matrix proteins, such as elastin and fibrillar collagens.1 Nonlysosomal cathepsin targets include degradation of matrix and bone via elastinolytic/collagenolytic activity, activation of pro-MMP, induction of anoikis-dependent apoptosis via matrix degradation, activation of caspases, and cleavage of focal adhesion kinases. A decade ago, measurement of cathepsin activity in heart tissue of different pathologies was used as a measure of lysosomal activity and …