Published online before print January 12, 2006, doi: 10.1161/01.ATV.0000203526.75772.4b
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Destabilizing Role of Cathepsin S in Murine Atherosclerotic Plaques
From the Bristol Heart Institute (K.J.R., D.J.W., A.L.M.), University of Bristol, United Kingdom; Heart Research Institute (P.Y.C.), Sydney, Australia; Pfizer Global Research and Development (W.H.B.), Groton, Conn; and Pfizer Central Research (C.J.L.), Sandwich, UK. K.J.R. is now at The Heart Research Institute, Sydney, Australia. A.L.M. is now at the Forensic Science Service Chepstow Laboratory, United Kingdom. C.J.L. is now at Organon Laboratories Ltd., Newhouse, Scotland.
Reprint requests to Dr Christopher Jackson, Bristol Heart Institute, University of Bristol, Level 7 Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom. E-mail chris.jackson{at}bristol.ac.uk
Objective— Lysosomal proteinases have been implicated in a number of pathologies associated with extracellular matrix breakdown. Therefore, we investigated the possibility that the lysosomal proteinase cathepsin S may be involved in atherosclerotic plaque destabilization.
Methods and Results— Atherosclerotic plaques in the brachiocephalic arteries of fat-fed apolipoprotein E/cathepsin S double knockout mice had 73% fewer acute plaque ruptures (P=0.026) and were 46% smaller (P=0.025) than those in age-, strain-, and sex-matched apolipoprotein E single knockout controls. When the incidence of acute plaque rupture was normalized for plaque size, the reduction in the double knockouts was 72% (P=0.039). The number of buried fibrous layers, indicative of an unstable plaque phenotype, was reduced by 67% in the double knockouts (P=0.008). The cysteine proteinase inhibitor, egg white cystatin, was biotinylated and used as an active-site-directed probe for cathepsins. Biotinylated cystatin selectively detected cathepsin S in extracts of human carotid atherosclerotic plaque. Active cathepsin S was detectable in extracts of human atherosclerotic plaque but not in nondiseased carotid arteries. Active cathepsins were especially prominent in macrophages in the shoulder regions of plaques, areas considered to be vulnerable to rupture. Cathepsin S protein colocalized with regions of elastin degradation in human coronary plaques.
Conclusion— These data provide direct evidence that an endogenous proteinase, cathepsin S, plays an important role in atherosclerotic plaque destabilization and rupture.
Apolipoprotein E knockout mice fed a high-fat diet rapidly develop unstable plaques in the brachiocephalic artery. Making these mice additionally null to the cysteine proteinase cathepsin S resulted in a significant reduction in plaque size and an independent reduction in the incidence of plaque rupture. Human atherosclerotic plaques contain active cysteine proteinases as detected with a novel active site-directed probe. These data support the idea that cathepsin S is a mediator of plaque destabilization and rupture.
Key Words: atherosclerosis • plaque • pathology • cathepsin
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]
|
|
|
|
 |
|
 E. Aikawa, M. Aikawa, P. Libby, J.-L. Figueiredo, G. Rusanescu, Y. Iwamoto, D. Fukuda, R. H. Kohler, G.-P. Shi, F. A. Jaffer, et al. Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease Circulation, April 7, 2009; 119(13): 1785 - 1794. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. de Nooijer, I. Bot, J.H. von der Thusen, M.A. Leeuwenburgh, H.S. Overkleeft, A.O. Kraaijeveld, R. Dorland, P.J. van Santbrink, S.H. van Heiningen, M.M. Westra, et al. Leukocyte Cathepsin S Is a Potent Regulator of Both Cell and Matrix Turnover in Advanced Atherosclerosis Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 188 - 194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Aoki, H. Kataoka, R. Ishibashi, K. Nozaki, and N. Hashimoto Cathepsin B, K, and S Are Expressed in Cerebral Aneurysms and Promote the Progression of Cerebral Aneurysms Stroke, September 1, 2008; 39(9): 2603 - 2610. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
C. L. Jackson, M. R. Bennett, E. A.L. Biessen, J. L. Johnson, and R. Krams Assessment of Unstable Atherosclerosis in Mice Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 714 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Novinec, R. N. Grass, W. J. Stark, V. Turk, A. Baici, and B. Lenarcic Interaction between Human Cathepsins K, L, and S and Elastins: MECHANISM OF ELASTINOLYSIS AND INHIBITION BY MACROMOLECULAR INHIBITORS J. Biol. Chem., March 16, 2007; 282(11): 7893 - 7902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Saloner, G. Acevedo-Bolton, M. Wintermark, and J. H. Rapp MRI of Geometric and Compositional Features of Vulnerable Carotid Plaque Stroke, February 1, 2007; 38(2): 637 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Jackson Ruptures of Delight?: A New Mouse Model of Plaque Rupture. Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1191 - 1192. [Full Text] [PDF]
|
|