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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2130.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Enzymatic Modification of Low-Density Lipoprotein in the Arterial Wall

A New Role for Plasmin and Matrix Metalloproteinases in Atherogenesis

Michael Torzewski; Prapat Suriyaphol; Kerstin Paprotka; Lena Spath; Viola Ochsenhirt; Andrea Schmitt; Shan-Rui Han; Matthias Husmann; Verena B. Gerl; Sucharit Bhakdi; Karl J. Lackner

From the Institutes of Clinical Chemistry and Laboratory Medicine (M.T., V.O., A.S., K.J.L.) and Medical Microbiology and Hygiene (P.S., K.P., L.S., S.-R.H., M.H., S.B.), and the Department of Ophthalmology (V.B.G.), University of Mainz, Germany.

Correspondence to Karl J. Lackner, Institute for Clinical Chemistry and Laboratory Medicine, University of Mainz, Langenbeckstr. 1, D-55131 Mainz, Germany (E-mail lackner{at}zentrallabor.klinik.uni-mainz.de) or Sucharit Bhakdi, Institute of Medical Microbiology and Hygiene, University of Mainz, Hochhaus am Augustusplatz, D-55101 Mainz, Germany (E-mail sbhakdi@uni-mainz.de)

Objective— Functionally interactive proteases of the plasminogen/plasmin and the matrix metalloproteinase (MMP) system degrade and reorganize the extracellular matrix of the vessel wall in atherosclerosis. Here we investigated whether such proteases are able to confer atherogenic properties onto low density lipoprotein by nonoxidative modification.

Methods and Results— Similar to the recently described enzymatically-modified low-density lipoprotein (E-LDL), native LDL exposed to plasmin or matrix MMP-2 or MMP-9 and cholesterylester-hydrolase (CEH) showed extensive deesterification, with ratios of free cholesterol to total cholesterol rising to 0.8 compared with 0.2 in native LDL. When the ratio exceeded 0.6, both plasmin/CEH-LDL and MMP/CEH-LDL fused into larger particles. In parallel, they gained C-reactive protein–dependent complement-activating capacity. E-LDL produced with any protease/CEH combination was efficiently taken up by human macrophages, whereby marked induction of MMP-2 expression by E-LDL was observed. These in vitro findings had their in vivo correlates: urokinase-type plasminogen activator, MMP-2, and MMP-9 were detectable in both early and advanced human atherosclerotic lesions in colocalization with E-LDL.

Conclusions— Plasmin and MMP-2/MMP-9 may not only be involved in remodeling of the extracellular matrix in progressing plaques, but they may also be involved in lipoprotein modification during genesis and progression of atherosclerotic lesions.

Plasmin and matrix metalloproteinases are present in early human atherosclerotic lesions. Both can synergize with cholesterylesterase to transform low-density lipoprotein into a molecule that binds C-reactive protein, activates complement, and induces macrophage foam cell formation. These processes may serve to remove stranded low-density lipoprotein from tissues, but excessive immune activation could trigger atherogenesis.

Key Words: atherosclerosis • lipoproteins • macrophages • metalloproteinases • plasminogen activators

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