Disruption of the Cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation

E. Lutgens, S. P.M. Lutgens, B. C.G. Faber, S. Heeneman, M. M.J. Gijbels, M. P.J. De Winther, P. Frederik, I. Van Der Made, A. Daugherty, A. M. Sijbers, A. Fisher, C. J. Long, P. Saftig, D. Black, M. J.A.P. Daemen, K. B.J.M. Cleutjens

Research output: Contribution to journalArticlepeer-review

196 Scopus citations

Abstract

BACKGROUND-: Cathepsin K (catK), a lysosomal cysteine protease, was identified in a gene-profiling experiment that compared human early plaques, advanced stable plaques, and advanced atherosclerotic plaques containing a thrombus, where it was highly upregulated in advanced stable plaques. METHODS AND RESULTS-: To assess the function of catK in atherosclerosis, catK/apolipoprotein (apo) E mice were generated. At 26 weeks of age, plaque area in the catK/apoE mice was reduced (41.8%) owing to a decrease in the number of advanced lesions as well as a decrease in individual advanced plaque area. This suggests an important role for catK in atherosclerosis progression. Advanced plaques of catK/apoE mice showed an increase in collagen content. Medial elastin fibers were less prone to rupture than those of apoE mice. Although the relative macrophage content did not differ, individual macrophage size increased. In vitro studies of bone marrow derived-macrophages confirmed this observation. Scavenger receptor-mediated uptake (particularly by CD36) of modified LDL increased in the absence of catK, resulting in an increased macrophage size because of increased cellular storage of cholesterol esters, thereby enlarging the lysosomes. CONCLUSIONS-: A deficiency of catK reduces plaque progression and induces plaque fibrosis but aggravates macrophage foam cell formation in atherosclerosis.

Original languageEnglish
Pages (from-to)98-107
Number of pages10
JournalCirculation
Volume113
Issue number1
DOIs
StatePublished - Jan 2006

Keywords

  • Atherosclerosis
  • Cathepsins
  • Lipids
  • Pathology
  • Proteases

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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