Role for cysteine protease cathepsins in heart disease: focus on biology and mechanisms with clinical implication.

The extracellular matrix (ECM) of the heart is composed largely of elastin and collagen and plays many roles in cardiac wall and valve homeostasis. Maintenance of a healthy cardiac system relies on controlled biosynthesis, maturation, function, and breakdown of ECM proteins. Dysregulation of proteolytic enzymes may disrupt these normal biological processes in myocardium-coronary-valve disease (CCVD). Substantial evidence supports the involvement of matrix metalloproteinase (MMP) and serine protease families in this process (reviewed elsewhere1,2). Cysteinyl proteases have received much less consideration in this regard, even though cardiovascular cells and macrophages with greatly expanded lysosomal compartments figure prominently in the pathogenesis of CCVD. Lysosomal cysteine proteases, generally known as cathepsins, were discovered in the second half of the 20th century. In the initial years after their discovery, cysteinyl cathepsins were shown to localize in lysosomes and endosomes and to function there to degrade unwanted intracellular or endocytosed proteins.3–5 However, the recent recognition of the inducible cathepsins F, K, S, B, and L led to the unraveling of their molecular functions in inflammatory and/or autoimmune diseases such as atherosclerosis,6–11 obesity,12–14 rheumatoid arthritis,15,16 cardiac repair,17 cardiomyopathy,18–20 and cancer.21 Most strikingly, we have now discovered that these cathepsins can be secreted into and function within the extracellular spaces. The observations of cathepsin expression and activity in failing cardiac tissues22–24 and valve tissues25–27 from humans and animals and in cultured media of cardiomyocytes,22,24 cardiac fibroblasts,22 vascular smooth muscle cells,28 endothelial cells,12 and macrophages6,10 have significantly broadened our understanding of their potential roles in cardiovascular pathogenesis. Furthermore, recent studies have shown that pharmacological cathepsin inhibition exhibits cardiovascular protective actions in animal models.23,24 In addition, accumulating evidence shows a prognostic and diagnostic impact of circulating and tissue cathepsins and/or the endogenous inhibitors known as cystatins in cardiovascular injury, remodeling, and function.8,14 This review focuses on recent findings in this field, highlighting the cathepsin biology and the significance of lysosomal cysteinyl proteases in ECM remodeling, pharmacological intervention, and prediction of the development and progression of heart disease.