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J. Biol. Chem., Vol. 279, Issue 33, 34776-34784, August 13, 2004

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Cysteine Protease Cathepsin F Is Expressed in Human Atherosclerotic Lesions, Is Secreted by Cultured Macrophages, and Modifies Low Density Lipoprotein Particles in Vitro^*

Katariina Öörni, Mia Sneck, Dieter Brömme¶, Markku O. Pentikäinen, Ken A. Lindstedt, Mikko Mäyränpää, Helena Aitio||, and Petri T. Kovanen

From the Wihuri Research Institute, FIN-00140 Helsinki, Finland, the ^¶Mount Sinai School of Medicine, the Department of Human Genetics, New York, New York 10029, and the ^||University of Helsinki, National Biological NMR Laboratory of Finland, FIN-00014 Helsinki, Finland

During atherogenesis, low density lipoprotein (LDL) particles in the arterial intima become modified and fuse to form extracellular lipid droplets. Proteolytic modification of apolipoprotein (apo) B-100 may be one mechanism of droplet formation from LDL. Here we studied whether the newly described acid protease cathepsin F can generate LDL-derived lipid droplets in vitro. Treatment of LDL particles with human recombinant cathepsin F led to extensive degradation of apoB-100, which, as determined by rate zonal flotation, electron microscopy, and NMR spectroscopy, triggered both aggregation and fusion of the LDL particles. Two other acid cysteine proteases, cathepsins S and K, which have been shown to be present in the arterial intima, were also capable of degrading apoB-100, albeit less efficiently. Cathepsin F treatment resulted also in enhanced retention of LDL to human arterial proteoglycans in vitro. Cultured monocyte-derived macrophages were found to secrete active cathepsin F. In addition, similarly with cathepsins S and K, cathepsin F was found to be localized mainly within the macrophage-rich areas of the human coronary atherosclerotic plaques. These results suggest that proteolytic modification of LDL by cathepsin F may be one mechanism leading to the extracellular accumulation of LDL-derived lipid droplets within the proteoglycan-rich extracellular matrix of the arterial intima during atherogenesis.

Received for publication, October 1, 2003 , and in revised form, June 3, 2004.

^* This work was supported by grants from the Academy of Finland (to K. Ö.) and the Sigrid Juselius Foundation (to M. S.), by Grant QLG1-1999-01007 from the European Commission to the consortium "Macrophage Function and Stability of the Atherosclerotic Plaque" as part of the Fifth Framework Programme of the European Union (to P. T. K. and M. O. P.), and by National Institutes of Health Grants AR46182 and AR 48669 (to D. B). 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: Wihuri Research Inst., Kalliolinnantie 4, FIN-00140 Helsinki, Finland. Tel.: 358-9-681-411; Fax: 358-9-637-476; E-mail: kati.oorni{at}wri.fi.

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