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(Circulation. 2007;115:2065-2075.)
© 2007 American Heart Association, Inc.

Vascular Medicine

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

Shiro Kitamoto, MD; Galina K. Sukhova, PhD; Jiusong Sun, PhD; Min Yang, MD, PhD; Peter Libby, MD; Victoria Love, PhD; Paurene Duramad, PhD; Chongxiu Sun, PhD; Yadong Zhang, PhD; Xiuwei Yang, PhD; Christoph Peters, PhD; Guo-Ping Shi, DSc

From the Departments of Medicine (S.K., G.K.S., J.S., M.Y., P.L., C.S., Y.Z., G.S.) and Pathology (V.L., P.D.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; Department of Medicine, Dana Farber Cancer Institute and Harvard Medical School (X.Y.), Boston, Mass; and Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg (C.P.), Freiburg, Germany.

Correspondence to Guo-Ping Shi, DSc, Cardiovascular Medicine, NRB-7, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail gshi{at}rics.bwh.harvard.edu

Received August 1, 2006; accepted January 30, 2007.

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.

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