This Article Full Text Full Text (PDF) All Versions of this Article: 96/3/368    most recent 01.RES.0000155964.34150.F7v1 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 Sukhova, G. K. Articles by Shi, G.-P. Search for Related Content PubMed PubMed Citation Articles by Sukhova, G. K. Articles by Shi, G.-P. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Related Collections Aneurysm, AVM, hematoma Mechanism of atherosclerosis/growth factors Animal models of human disease Pathophysiology

(Circulation Research. 2005;96:368.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Cystatin C Deficiency Increases Elastic Lamina Degradation and Aortic Dilatation in Apolipoprotein E–Null Mice

Galina K. Sukhova, Bing Wang, Peter Libby, Jie-Hong Pan, Yaou Zhang, Anders Grubb, Kenneth Fang, Harold A. Chapman, Guo-Ping Shi

From the Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, Mass; the Department of Medicine (G.K.S., B.W., P.L., G.-P.S.), University of California San Francisco (J.-H.P., Y.Z., K.F., H.A.C.), Calif; and the Department of Clinical Chemistry (A.G.), University of Lund, Sweden.

Correspondence to Guo-Ping Shi, DSc, Cardiovascular Medicine, NRB-7, 77 Ave Louis Pasteur, Boston, MA 02115. E-mail gshi{at}rics.bwh.harvard.edu

The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves substantial proteolysis of the arterial extracellular matrix. The lysosomal cysteine proteases can exert potent elastolytic and collagenolytic activity. Human atherosclerotic plaques have increased cysteine protease content and decreased levels of the endogenous inhibitor cystatin C, suggesting an imbalance that would favor matrix degradation in the arterial wall. This study tested directly the hypothesis that impaired expression of cystatin C alters arterial structure. Cystatin C–deficient mice (Cyst C^–/–) were crossbred with apolipoprotein E–deficient mice (ApoE^–/–) to generate cystatin C and apolipoprotein E–double deficient mice (Cyst C^–/–ApoE^–/–). After 12 weeks on an atherogenic diet, cystatin C deficiency yielded significantly increased tunica media elastic lamina fragmentation, decreased medial size, and increased smooth muscle cell and collagen content in aortic lesions of ApoE^–/– mice. Cyst C^–/–ApoE^–/– mice also showed dilated thoracic and abdominal aortae compared with control ApoE^–/– mice, although atheroma lesion size, intimal macrophage accumulation, and lipid core size did not differ between these mice. These findings demonstrate directly the importance of cysteine protease/protease inhibitor balance in dysregulated arterial integrity and remodeling during experimental atherogenesis.

Key Words: cystatin C • apolipoprotein E • cysteine protease • atherosclerosis • smooth muscle cells

This article has been cited by other articles:

				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]

				Y. S. Chatzizisis, M. Jonas, A. U. Coskun, R. Beigel, B. V. Stone, C. Maynard, R. G. Gerrity, W. Daley, C. Rogers, E. R. Edelman, et al. Prediction of the Localization of High-Risk Coronary Atherosclerotic Plaques on the Basis of Low Endothelial Shear Stress: An Intravascular Ultrasound and Histopathology Natural History Study Circulation, February 26, 2008; 117(8): 993 - 1002. [Abstract] [Full Text] [PDF]

				F. Schneider, G. K. Sukhova, M. Aikawa, J. Canner, N. Gerdes, S.-M. T. Tang, G.-P. Shi, S. S. Apte, and P. Libby Matrix Metalloproteinase-14 Deficiency in Bone Marrow-Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques Circulation, February 19, 2008; 117(7): 931 - 939. [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]

				J. D. Chang, G. K. Sukhova, P. Libby, E. Schvartz, A. H. Lichtenstein, S. J. Field, C. Kennedy, S. Madhavarapu, J. Luo, D. Wu, et al. Deletion of the phosphoinositide 3-kinase p110{gamma} gene attenuates murine atherosclerosis PNAS, May 8, 2007; 104(19): 8077 - 8082. [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]

				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]

				M. O. Platt, R. F. Ankeny, G.-P. Shi, D. Weiss, J. D. Vega, W. R. Taylor, and H. Jo Expression of cathepsin K is regulated by shear stress in cultured endothelial cells and is increased in endothelium in human atherosclerosis Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1479 - H1486. [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]

				M. O. Platt, R. F. Ankeny, and H. Jo Laminar Shear Stress Inhibits Cathepsin L Activity in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1784 - 1790. [Abstract] [Full Text] [PDF]

				K. Shimizu, R. N. Mitchell, and P. Libby Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 987 - 994. [Abstract] [Full Text] [PDF]

				B. Wang, J. Sun, S. Kitamoto, M. Yang, A. Grubb, H. A. Chapman, R. Kalluri, and G.-P. Shi Cathepsin S Controls Angiogenesis and Tumor Growth via Matrix-derived Angiogenic Factors J. Biol. Chem., March 3, 2006; 281(9): 6020 - 6029. [Abstract] [Full Text] [PDF]

				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, et al. Disruption of the Cathepsin K Gene Reduces Atherosclerosis Progression and Induces Plaque Fibrosis but Accelerates Macrophage Foam Cell Formation Circulation, January 3, 2006; 113(1): 98 - 107. [Abstract] [Full Text] [PDF]

				E. Bengtsson, F. To, K. Hakansson, A. Grubb, L. Branen, J. Nilsson, and S. Jovinge Lack of the Cysteine Protease Inhibitor Cystatin C Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2151 - 2156. [Abstract] [Full Text] [PDF]