Lysosomal cysteine proteases in atherosclerosis.
Atherosclerosis is an inflammatory disease characterized by extensive remodeling of the extracellular matrix architecture of the arterial wall. Although matrix metalloproteinases and serine proteases participate in these pathologic events, recent data from atherosclerotic patients and animals suggest the participation of lysosomal cysteine proteases in atherogenesis. Atherosclerotic lesions in humans overexpress the elastolytic and collagenolytic cathepsins S, K, and L but show relatively reduced expression of cystatin C, their endogenous inhibitor, suggesting a shift in the balance between cysteine proteases and their inhibitor that favors remodeling of the vascular wall. Extracts of human atheromatous tissue show greater elastolytic activity in vitro than do those from healthy donors. The cysteinyl protease inhibitor E64d limits this increased elastolysis, indicating involvement of cysteine proteases in elastin degradation during atherogenesis. Furthermore, inflammatory cytokines augment expression and secretion of active cysteine proteases from cultured monocyte-derived macrophages, vascular smooth muscle cells, and endothelial cells and increase degradation of extracellular elastin and collagen. Cathepsin S-deficient cells or those treated with E64d show significantly impaired elastolytic or collagenolytic activity. Additionally, recent in vivo studies of atherosclerosis-prone, LDL receptor-null mice lacking cathepsin S show participation of this enzyme in the initial infiltration of leukocytes, medial elastic lamina degradation, endothelial cell invasion, and neovascularization, illustrating an important role for cysteine proteases in arterial remodeling and atherogenesis.
Liu
Jian
J
Department of Molecular and Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, Anhui, China.
Sukhova
Galina K
GK
Sun
Jiu-Song
JS
Xu
Wei-Hua
WH
Libby
Peter
P
Shi
Guo-Ping
GP
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D055316:Cystatin C; D015891:Cystatins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000201:enzymology; D004790:Enzyme Induction; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000473:pathology; D008247:Lysosomes / Q000201:enzymology*; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013923:Thromboembolism / Q000209:etiology
D001057:Apolipoproteins E; C525030:CST3 protein, human; C525031:Cst3 protein, mouse; D055316:Cystatin C; D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D011973:Receptors, LDL; D003546:Cysteine Endopeptidases