CARDIAC REMODELING REFERS to the changes in cardiac structure and function that develop in response to a variety of stimuli, including inflammatory and neurohormonal mediators and increases in wall stress. While some forms of remodeling are physiologically compensatory, such as the changes in cardiac structure that occur over time with strenuous exercise, others are maladaptive and their persistence causes a progressive worsening of cardiac function that leads to heart failure. A strong association between cardiac remodeling and mortality has been noted in heart failure patients (16). Pressure overload is an important cause of remodeling in human patients as it can occur from conditions such as hypertension or chamber outflow obstruction that are common in the population. Changes that occur in the heart in response to increases in pressure include cardiomyocyte hypertrophy and enhanced deposition of extracellular matrix proteins (ie, fibrosis). Although some of these changes help compensate for increases in wall stress, over time they prove to be maladaptive as they result in abnormalities in both systolic and diastolic function (4). Although many of the pathways involved in the development of pressure overload remodeling have been identified, a full description of all of the “players” that contribute to the process is not yet available. Identification of novel pathways may help define novel strategies to prevent or reverse remodeling. Cathepsins are lysosomal proteases contributing to autophagic degradation of cellular substrates (30). They are composed of 11 members (cathepsin B, C, F, H, K, L, O, S, V, X, and W), most of which are ubiquitously expressed in living organisms (30). Cathepsins play a role in a number of signaling pathways and appear to be associated with several diseases, including neurological disorders (23), cancers (28), and cardiomyopathies (18). Increased cathepsin gene expression was reported in conditions of cardiac stress, remodeling, and dysfunction. Cathepsin S and K were found increased in pressure overload-induced myocardium of rodents and in humans with hypertension-induced heart failure (2). Cathepsin D was found to be elevated in the plasma of patients after myocardial infarction (MI)(21).

Validation for the important roles of cathepsins in the heart and during cardiac pathogenesis came recently from studies of cathepsin K, L, S, and D knockout mice. Loss of cathepsin K alleviates both pressure overload-induced and high-fat dietinduced cardiac hypertrophy, likely through the inhibition of mammalian target of rapamycin (mTOR) and ERK pathways (13, 14). On the contrary, several other cathepsins were found to be cardioprotective. Loss of cathepsin L promoted cardiac hypertrophy upon stress, which was associated with accumulation of protein substrates such as α-actinin, myosin, connexin-43, and H-cadherin (27). Moreover, cathepsin S seems to