Cysteinyl Cathepsins: Multifunctional Enzymes in Cardiovascular Disease

Abstract

Until recently, the role of lysosomal cysteine protease cathepsins in intracellular protein degradation was believed to be mainly restricted to scavenging. However, recent studies have revealed nontraditional roles for cysteine protease cathepsins in the extracellular space during the development and progression of cardiovascular disease. Although the precise mechanisms are unknown, data from animal studies suggest that members of the cathepsin family, like other extracellular proteases, contribute to extracellular matrix protein remodeling and interstitial matrix degradation, as well as to cell signaling and cell apoptosis in heart disease. Inflammatory cytokines and hormones regulate the expression and secretion of cathepsins in cultured cardiovascular cells and macrophages. Serum levels of cathepsins L, S, and K and their endogenous inhibitor cystatin C may be useful predictive biomarkers in patients with coronary artery disease and cardiac disease. Furthermore, in vivo pharmacological intervention with a synthetic cathepsin inhibitor and cardiovascular drugs (including statins and angiotensin II type 1 receptor antagonists) has the potential for pharmacologic targeting of cathepsins in cardiovascular disease. This review focuses on cathepsin biology (structure, synthesis, processing, activation, secretion, activity regulation, and function) and the involvement of cysteinyl cathepsins in the pathogenesis of several heart and vessel diseases, especially with respect to their potential application as diagnostic and prognostic markers and drug targets to prevent inappropriate proteolysis in cardiovascular disease.

Cathepsins Limit Macrophage Necroptosis through Cleavage of Rip1 Kinase

“…Interestingly, expression of both cathepsin S and B has been well documented at inflammatory sites in various disease models including pancreatitis (39), inflammatory bowel disease (40), and atherosclerosis (41). It seems plausible that cathepsin-mediated cleavage of Rip1 kinase could play a role in perpetuating macrophage survival and function within inflammatory sites.…”

l‐Homocysteine‐induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia

“…Cathepsins are released by endothelial cells that sense and respond to TNF‐α (Keegan et al ., ). The serum levels of cathepsins are associated with inflammatory cytokine levels in patients with cardiovascular diseases (Li et al ., ). However, it was recently reported that cathepsin V, which is specifically expressed in humans (Zhou et al ., ), increases the expression of the inflammatory cytokine TNF‐α in macrophages (Pribis et al ., ).…”

Effects of intermittent exercise on biomarkers of cardiovascular risk in night shift workers

“…Cathepsin L (CatL), Cathepsin S (CatS), and Cathepsin K (CatK) release proteases to degrade extracellular collagen and elastin in the arterial wall, thus promoting atherogenesis [5]. Furthermore, cysteinyl Cats may have certain biological roles and molecular functions in vascular pathological processes, and may hence have potential application as diagnostic or prognostic markers [6]. Additionally, atherosclerotic lesions demonstrate an increased expression of chemokines such as chemotactic protein-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin) in endothelial cells of plaque microvessels or in endothelial cells overlying the lipid core-a response that may contribute to further leukocyte recruitment to sites of atherosclerosis [7].…”