Cathepsin L Deficiency Reduces Diet-Induced Atherosclerosis in Low-Density Lipoprotein Receptor–Knockout Mice
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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) double-deficient (LDLr−/−Cat L−/−) mice by crossbreeding Cat L–null (Cat L−/−) and LDLr-deficient (LDLr−/−) mice. After 12 and 26 weeks of a Western diet, LDLr−/−Cat L−/− mice had significantly smaller atherosclerotic lesions and lipid cores compared with littermate control LDLr−/−Cat L+/− and LDLr−/−Cat L+/+ mice. In addition, lesions from the compound mutant mice showed significantly reduced levels of collagen, medial elastin degradation, CD4+ 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−/−Cat L−/− 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.
Received August 1, 2006; accepted January 30, 2007.