title: 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.
  
  
  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.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass, USA.
authors.forename: Shiro
authors.initials: S
authors.lastname: Kitamoto
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Victoria
authors.initials: V
authors.lastname: Love
authors.forename: Paurene
authors.initials: P
authors.lastname: Duramad
authors.forename: Chongxiu
authors.initials: C
authors.lastname: Sun
authors.forename: Yadong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiuwei
authors.initials: X
authors.lastname: Yang
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D050197:Atherosclerosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D056668:Cathepsin L; D002403:Cathepsins / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D002633:Chemotaxis / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000172:deficiency* / Q000235:genetics; D004036:Diet, Atherogenic; D018450:Disease Progression; D042783:Endothelial Cells / Q000166:cytology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
chemical_list: D008055:Lipids; D011973:Receptors, LDL; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse