Enzymatic modification of low-density lipoprotein in the arterial wall: a new role for plasmin and matrix metalloproteinases in atherogenesis.
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.


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.
Torzewski
Michael
M
Institute for Clinical Chemistry and Laboratory Medicine, University of Mainz, Mainz, Germany.
Suriyaphol
Prapat
P
Paprotka
Kerstin
K
Spath
Lena
L
Ochsenhirt
Viola
V
Schmitt
Andrea
A
Han
Shan-Rui
SR
Husmann
Matthias
M
Gerl
Verena B
VB
Bhakdi
Sucharit
S
Lackner
Karl J
KJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001161:Arteriosclerosis / Q000201:enzymology* / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002097:C-Reactive Protein / Q000502:physiology; D002478:Cells, Cultured; D003167:Complement Activation / Q000502:physiology; D015941:Complement Hemolytic Activity Assay / Q000379:methods; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005341:Fibrinolysin / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000201:enzymology; D012967:Sodium Dodecyl Sulfate / Q000378:metabolism; D002787:Sterol Esterase / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D000911:Antibodies, Monoclonal; D008077:Lipoproteins, LDL; D012967:Sodium Dodecyl Sulfate; D002097:C-Reactive Protein; D002787:Sterol Esterase; D014357:Trypsin; D005341:Fibrinolysin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9