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Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels

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Abstract

Several growth factors, chemokines, adhesion molecules, and proteolytic enzymes important for cell–cell/cell–matrix interactions in atherosclerosis and restenosis are initially synthesized as inactive precursor proteins. Activation of proproteins to biologically active molecules is regulated by limited endoproteolytic cleavage at dibasic amino acid residues. This type of activation typically requires the presence of suitable proprotein convertases (PCs). The PC-isozymes furin and PC5 are expressed in human atherosclerotic lesions and have been found to be up-regulated, following vascular injury in animal models in vivo. In vitro, these PCs can regulate vascular smooth muscle cell and macrophage functions and signaling events, through activation of pro-α-integrins and/or pro-membrane-type matrix metalloproteinases. Integrins link the cytoskeleton with the extracellular matrix and mediate bidirectional signaling and mechanotransduction, whereas matrix metalloproteinases are the major matrix-degrading enzymes. Both activities are required for cell recruitment to the intima. Furthermore, cleavage of extracellular matrix molecules by matrix metalloproteinases potentially contributes to weakening of the fibrous cap, promoting plaque rupture. Based on these recent in vitro and in vivo data, furin and PC5 are potential contributors to the initiation, progression, and complications of atherosclerosis and restenosis. Targeting these PCs may provide future anti-atherosclerotic therapies.

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Acknowledgements

The authors thank Ms. A. Gaußmann for help with the preparation of Figs. 3 and 4. The work of the authors was supported by the Bundesministerium für Bildung und Forschung (CAN02/005) and an independent research grant from Philip Morris USA Inc. and Philip Morris International.

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  1. Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Philipp Stawowy & Eckart Fleck

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Correspondence to Philipp Stawowy.

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Stawowy, P., Fleck, E. Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels. J Mol Med 83, 865–875 (2005). https://doi.org/10.1007/s00109-005-0723-8

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