Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice

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

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

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 (LDLrCat L) mice by crossbreeding Cat L-null (Cat L) and LDLr-deficient (LDLr) mice. After 12 and 26 weeks of a Western diet, LDLrCat L mice had significantly smaller atherosclerotic lesions and lipid cores compared with littermate control LDLrCat L and LDLrCat 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 LDLrCat 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.

Original languageEnglish
Pages (from-to)2065-2075
Number of pages11
JournalCirculation
Volume115
Issue number15
DOIs
StatePublished - Apr 2007

Keywords

  • Atherosclerosis
  • Cathepsin L
  • Collagen
  • Elastin
  • Metalloproteinases
  • Receptors, LDL
  • Remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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