Fig. 2

The roles of cathepsins in atherosclerosis (AS). The phases of AS initiation and its complications are shown. Upper panel: Cross-section of a plaque formation. The image at left part of the panel depicts the AS initiation stage: cathepsins can modulate the productions of chemokines such as CXC-chemokine ligand 12 (CXCL12), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecular-1 (VCAM-1), which triggers the recruitment of inflammatory cells (neutrophils and macrophages), immune cells (T cells) and endothelial progenitor cells (EPC), adhesion, transmigration, antigen presentation/activation, and proliferation and/or differentiation in the vascular wall. The image at right part of the panel shows plaque containing abundant macrophage foam cells, lipids and necrotic debris, hemmed by a fibrous cap comprised of a collagen-rich matrix. Cathepsins participate in multiple events, including collagen degradation and elastin fragmentation, EPC and endothelial cell migration and vaso vasorum formation, oxidative low-density lipoprotein (OxLDL) degradation to aggregation and accumulation, high density lipoprotein (HDL) degradation to cholesterol efflux reduction, macrophage and smooth muscle cell (SMC)-derived foam cell formation, SMC transmigration and proliferation, and vascular and inflammatory cell apoptosis. Lower panel: Cross-section of plaque rupture, thrombosis, and stent-in-restenosis. As shown at the left, rupture of the fibrosis cap by CVD-related cell-derived cathepsins takes place at the endothelial denudation phase, which triggers the exposure of the highly thrombogenic necrotic core, leading to platelet activation and aggregation and thrombosis and the triggering of a cascade of proteolytic processes such as the releases of CTSG, urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) by vascular disease cells, facilitating fibrin degradation and lysis of the thrombus. As shown in the middle part of depicting calcification, several factors (AGE, AngII, and CaPO4) trigger the expression of nuclear factor of activated T cells c-1 (NFATc-1) through modulation of either a RANKL/RANK-mediated ERK/e-fos or p38MAPK signaling pathway, which induces calcium mineralization that mediates CTSK in CD68+ MR+ CA2+ CTSKlow cells (called “dysfunctional osteoclast-like cells”). As shown at the right part of depicting stent-in-restenosis, CTSK triggers oxidative stress-induced apoptosis via pro-caspase-8 (pro-Cas-8) maturation, which produces proliferin-1 to stimulate media smooth-muscle repopulation and the development of injury-related hyperplasia/stent-in-restenosis in humans and animals via the activation of a mannose-6-phosphate receptor (M6PR) signaling cascade. CA2: carbonic anhydrase type II; CTS: cathepsin; ERK: extracellular signal-regulated kinase; GM-AGE: glycoladehyde-modified advanced glycation endproducts; IL: interleukin; MITF: microphthalmia transcription factor; p38MAPK: p38 mitogen-activated protein kinase; RANK: receptor of activator of nuclear factor-κB; RANKL: RANK ligand