This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 113/1/98    most recent CIRCULATIONAHA.105.561449v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lutgens, E. Articles by Cleutjens, K.B.J.M. Search for Related Content PubMed PubMed Citation Articles by Lutgens, E. Articles by Cleutjens, K.B.J.M. Related Collections Pathophysiology Genetically altered mice Genomics Other Vascular biology

(Circulation. 2006;113:98-107.)
© 2006 American Heart Association, Inc.

Vascular Medicine

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; 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.

Correspondence to E. Lutgens, MD, PhD, Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. E-mail E.Lutgens{at}path.unimaas.nl

Received May 22, 2005; revision received September 25, 2005; accepted October 20, 2005.

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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				N. Taglieri, W. Koenig, and J. C. Kaski Cystatin C and Cardiovascular Risk Clin. Chem., November 1, 2009; 55(11): 1932 - 1943. [Abstract] [Full Text] [PDF]

				Y. Sun, M. Ishibashi, T. Seimon, M. Lee, S. M. Sharma, K. A. Fitzgerald, A. O. Samokhin, Y. Wang, S. Sayers, M. Aikawa, et al. Free Cholesterol Accumulation in Macrophage Membranes Activates Toll-Like Receptors and p38 Mitogen-Activated Protein Kinase and Induces Cathepsin K Circ. Res., February 27, 2009; 104(4): 455 - 465. [Abstract] [Full Text] [PDF]

				J. Guo, I. Bot, R. de Nooijer, S. J. Hoffman, G. B. Stroup, E. A.L. Biessen, G. M. Benson, P. H.E. Groot, M. Van Eck, and T. J.C. Van Berkel Leucocyte cathepsin K affects atherosclerotic lesion composition and bone mineral density in low-density lipoprotein receptor deficient mice Cardiovasc Res, February 1, 2009; 81(2): 278 - 285. [Abstract] [Full Text] [PDF]

				O. Hofnagel and H. Robenek Cathepsin K: boon or bale for atherosclerotic plaque stability? Cardiovasc Res, February 1, 2009; 81(2): 242 - 243. [Full Text] [PDF]

				J.-F. Cailhier, I. Sirois, P. Laplante, S. Lepage, M.-A. Raymond, N. Brassard, A. Prat, R. V. Iozzo, A. V. Pshezhetsky, and M.-J. Hebert Caspase-3 Activation Triggers Extracellular Cathepsin L Release and Endorepellin Proteolysis J. Biol. Chem., October 3, 2008; 283(40): 27220 - 27229. [Abstract] [Full Text] [PDF]

				C. L. Welch, Y. Sun, B. J. Arey, V. Lemaitre, N. Sharma, M. Ishibashi, S. Sayers, R. Li, A. Gorelik, N. Pleskac, et al. Spontaneous Atherothrombosis and Medial Degradation in Apoe-/-, Npc1-/- Mice Circulation, November 20, 2007; 116(21): 2444 - 2452. [Abstract] [Full Text] [PDF]

				S. P. M. Lutgens, K. B. J. M. Cleutjens, M. J. A. P. Daemen, and S. Heeneman Cathepsin cysteine proteases in cardiovascular disease FASEB J, October 1, 2007; 21(12): 3029 - 3041. [Abstract] [Full Text] [PDF]

				E. Suganuma, V. R. Babaev, M. Motojima, Y. Zuo, N. Ayabe, A. B. Fogo, I. Ichikawa, M. F. Linton, S. Fazio, and V. Kon Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2311 - 2319. [Abstract] [Full Text] [PDF]

				Y. S. Chatzizisis, A. U. Coskun, M. Jonas, E. R. Edelman, C. L. Feldman, and P. H. Stone Role of Endothelial Shear Stress in the Natural History of Coronary Atherosclerosis and Vascular Remodeling: Molecular, Cellular, and Vascular Behavior J. Am. Coll. Cardiol., June 26, 2007; 49(25): 2379 - 2393. [Abstract] [Full Text] [PDF]

				F. A. Jaffer, D.-E. Kim, L. Quinti, C.-H. Tung, E. Aikawa, A. N. Pande, R. H. Kohler, G.-P. Shi, P. Libby, and R. Weissleder Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor Circulation, May 1, 2007; 115(17): 2292 - 2298. [Abstract] [Full Text] [PDF]

				S. Kitamoto, G. K. Sukhova, J. Sun, M. Yang, P. Libby, V. Love, P. Duramad, C. Sun, Y. Zhang, X. Yang, et al. Cathepsin L Deficiency Reduces Diet-Induced Atherosclerosis in Low-Density Lipoprotein Receptor-Knockout Mice Circulation, April 17, 2007; 115(15): 2065 - 2075. [Abstract] [Full Text] [PDF]

				X. W. Cheng, K. Obata, M. Kuzuya, H. Izawa, K. Nakamura, E. Asai, T. Nagasaka, M. Saka, T. Kimata, A. Noda, et al. Elastolytic Cathepsin Induction/Activation System Exists in Myocardium and Is Upregulated in Hypertensive Heart Failure Hypertension, November 1, 2006; 48(5): 979 - 987. [Abstract] [Full Text] [PDF]