Cathepsin L Deficiency Reduces Diet-Induced Atherosclerosis in Low-Density Lipoprotein Receptor–Knockout Mice

Abstract

Background-Remodeling of the arterial extracellular matrix participates importantly in atherogenesis and plaque complication. Increased expression of the elastinolytic and collagenolytic enzyme cathepsin L (Cat L) in human atherosclerotic lesions suggests its participation in these processes, a hypothesis tested here in mice. Methods and Results-We generated Cat L and low-density lipoprotein receptor (LDLr) ϩ T cells, macrophages, and smooth muscle cells. Mechanistic studies showed that Cat L contributes to the degradation of extracellular matrix elastin and collagen by aortic smooth muscle cells. Smooth muscle cells from LDLr Ϫ/Ϫ Cat L Ϫ/Ϫ mice or those treated with a Cat L-selective inhibitor demonstrated significantly less degradation of elastin and collagen and delayed transmigration through elastin in vitro. Cat L deficiency also significantly impaired monocyte and T-lymphocyte transmigration through a collagen matrix in vitro, suggesting that blood-borne leukocyte penetration through the arterial basement membrane requires Cat L. Cysteine protease active site labeling demonstrated that Cat L deficiency did not affect the activity of other atherosclerosis-associated cathepsins in aortic smooth muscle cells and monocytes. Conclusions-Cat L directly participates in atherosclerosis by degrading elastin and collagen and regulates blood-borne leukocyte transmigration and lesion progression.

Peroxisome Proliferator-activated Receptor γ Induces Apoptosis and Inhibits Autophagy of Human Monocyte-derived Macrophages via Induction of Cathepsin L

“…On this background, our results would imply that the PPAR␥-mediated increase in CatL expression in macrophages may represent a new approach for the inhibition of atherosclerosis progression. However, CatL was reported to induce rather than to reduce the progression of atherosclerosis (6,12).…”

“…Among them, cathepsin L (CatL) 3 is one of the most potent collagenases and elastases cleaving mature insoluble elastin (3). CatB (4,5) and CatL (6,7) expression is enhanced in human coronary lesions, but also in human carotid lesions and abdominal aortic aneurysms (8). CatK, CatS, and CatF are also expressed in human atherosclerotic lesions (9,10), and CatB, CatD, and CatL were found in macrophage-derived foam cells in lipid-rich plaque areas (11).…”

“…CatK, CatS, and CatF are also expressed in human atherosclerotic lesions (9,10), and CatB, CatD, and CatL were found in macrophage-derived foam cells in lipid-rich plaque areas (11). The pathophysiological role of Cat is underlined by the findings that deficiency of CatS and CatL in LDL receptor knock-out mice reduced atherosclerotic lesions (6,12). Of note, unstable plaque regions contain increased levels of active legumain, a cysteine protease that promotes intracellular processing of CatL to its mature 25-kDa form (13).…”

Caspase-3 Activation Triggers Extracellular Cathepsin L Release and Endorepellin Proteolysis

“…Other ECM-degrading activities of CathL on elastin and collagen are also of potential importance in the development of atherosclerotic diseases. CathL and LDL receptor double-deficient mice were recently found to be protected from the development of atherosclerotic lesions, compared with LDL receptor-deficient mice, and manifested reduced medial elastin degradation (42). Protein levels and CathL activity were elevated within the vascular wall of patients with abdominal aortic aneurysm, a disease that typifies extensive ECM degradation and vascular remodeling (37,54,55).…”

Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

“…Although defects in macrophage infiltration have been reported in different knock-out mice models [52][53][54][55], a comprehensive investigation into the 3D migration of macrophages has only recently begun because experimental models and suitable techniques needed to be developed first. 3D migration models in vitro, such as Matrigel invasion assays, have started to shed light on the migration modes used by macrophages, and the involvement of the different protease sub-families.…”