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Matrix metalloproteinases (MMPs) can degrade a number of proteins that constitute the extracellular matrix. Previous studies have shown that atherosclerotic plaques contain substantial amounts of fibrin(ogen)-related antigen, and more recently, MMPs have been identified in such lesions. The hypothesis that MMPs play a role in the degradation of fibrinogen (Fg) and cross-linked fibrin (XL-Fb) was investigated. Fibrinogen became thrombin-unclottable when treated with matrix metalloproteinase 3 (MMP-3, stromelysin 1) but not with matrix metalloproteinase 2 (MMP-2, gelatinase A). Incubation of XL-Fb clots (made with 125I-Fg) with MMP-3 resulted in complete lysis after 24 h. A D monomer-like fragment was generated by MMP-3 degradation of fibrinogen, XL-Fb, and fragment DD. Immunoreactivity with monoclonal antibody (MoAb)/4-2 (anti-gamma 392-406) but not with MoAb/4A5 (anti-gamma 397-411) suggested that a major cleavage site was within the sequence participating in the cross-linking of two gamma-chains. NH2-terminal sequence analysis of they gamma-chain of the D monomer-like fragment and of a dipeptide isolated from the MMP-3 digest of XL-fibrin identified the hydrolysis of the gamma Gly 404-Ala 405 peptide bond. These data indicate that the degradation of Fg and XL-Fb by MMP-3 is specific and different from plasmin. This mechanism of fibrinolysis might be of relevance in wound healing, inflammation, atherosclerosis, and other pathophysiological processes.

Original publication

DOI

10.1021/bi960730c

Type

Journal article

Journal

Biochemistry

Publication Date

10/1996

Volume

35

Pages

13056 - 13063

Addresses

Laboratory of Blood Coagulation Biochemistry, Lindsley F. Kimball Research Institute, New York Blood Center, New York 10021, USA. abini@server.nybc.org

Keywords

Humans, Cyanogen Bromide, Metalloendopeptidases, Collagenases, Gelatinases, Plasmin, Glutamine, Peptides, Fibrinogen, Fibrin, Fibrin Fibrinogen Degradation Products, Antibodies, Monoclonal, Sequence Analysis, Amino Acid Sequence, Protein Conformation, Substrate Specificity, Blood Coagulation, Molecular Sequence Data, Matrix Metalloproteinase 2, Matrix Metalloproteinase 3, Matrix Metalloproteinase 1