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

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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) 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 colla...

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