Published Online
on December 19, 2005

A more recent version of this article appeared on January 3, 2006

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Submitted on May 22, 2005
Revised on September 25, 2005
Accepted on October 20, 2005

Disruption of the Cathepsin K Gene Reduces Atherosclerosis Progression and Induces Plaque Fibrosis but Accelerates Macrophage Foam Cell Formation

E. Lutgens MD, PhD^*, S. P.M. Lutgens MSc, B. C.G. Faber PhD, S. Heeneman PhD, M. M.J. Gijbels PhD, M. P.J. de Winther PhD, P. Frederik PhD, I. van der Made MSc, A. Daugherty PhD, A. M. Sijbers PhD, A. Fisher PhD, C. J. Long PhD, P. Saftig PhD, D. Black PhD, M. J.A.P. Daemen MD, PhD, and K. B.J.M. Cleutjens PhD

From the Departments of Pathology (E.L., S.P.M.L., B.C.G.F., S.H., M.M.J.G., M.J.A.P.D., K.B.J.M.C.), Molecular Genetics (M.M.J.G., M.P.J.d.W., I.v.d.M.), and Electron Microscopy (P.F.), Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, the Netherlands; the University of Kentucky (A.D.), Lexington; Organon Scotland (A.M.S., A.F., C.J.L., D.B.), Newhouse, Scotland; and the Biochemical Institute (P.S.), University of Kiel, Kiel, Germany.

^* To whom correspondence should be addressed. E-mail: E.Lutgens{at}path.unimaas.nl.

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.

Key words: atherosclerosis • lipids • pathology • proteases • cathepsins

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