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J. Biol. Chem., Vol. 279, Issue 35, 36761-36770, August 27, 2004

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Cathepsin V, a Novel and Potent Elastolytic Activity Expressed in Activated Macrophages^*

Yoshiyuki Yasuda, Zhenqiang Li, Doron Greenbaum, Matthew Bogyo¶, Ekkehard Weber||, and Dieter Brömme**

From the Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, the Walter and Eliza Hall Institute for Medical Research, Parkville, Australia 3050, the ^¶Department of Pathology, Stanford University, Palo Alto, California 94305, and the ^||Institute of Physiological Chemistry, Martin-Luther-University, Hollystr. 1 06114 Halle (Saale) Germany

Atherosclerosis is characterized by a thickening and loss of elasticity of the arterial wall. Loss of elasticity has been attributed to the degradation of the arterial elastin matrix. Cathepsins K and S are papain-like cysteine proteases with known elastolytic activities, and both enzymes have been identified in macrophages present in plaque areas of diseased blood vessels. Here we demonstrate that macrophages express a third elastolytic cysteine protease, cathepsin V, which exhibits the most potent elastase activity yet described among human proteases and that cathepsin V is present in atherosclerotic plaque specimens. Approximately 60% of the total elastolytic activity of macrophages can be attributed to cysteine proteases with cathepsins V, K, and S contributing equally. From this 60%, two-thirds occur extracellularly and one-third intracellularly with the latter credited to cathepsin V. Ubiquitously expressed glycosaminoglycans (GAGs) such as chondroitin sulfate specifically inhibit the elastolytic activities of cathepsins V and K via the formation of specific cathepsin-GAG complexes. In contrast, cathepsin S, which does not form complexes with chondroitin sulfate is not inhibited; thus suggesting a specific regulation of elastolytic activities of cathepsins by GAGs. Because the GAG content is reduced in atherosclerotic plaques, an increase of cathepsins V and K activities may accelerate the destruction of the elastin matrix in diseased arteries.

Received for publication, April 9, 2004 , and in revised form, June 8, 2004.

^* This work was supported by National Institutes of Health Grants AR46182 and AR48669. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Human Genetics, Mount Sinai School of Medicine, Box 1498, 5th Ave. 100th St., New York, NY 10029. E-mail: dieter.bromme{at}mssm.edu.

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