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.