Granulocytes in coronary thrombus evolution after myocardial infarction--time-dependent changes in expression of matrix metalloproteinases.
BACKGROUND
Remodeling of extracellular matrix is a key process during wound healing, which is strictly regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors [tissue inhibitors of metalloproteinases (TIMPs)]. In this study, we evaluated intrathrombotic MMPs and TIMPs and their cellular origin during thrombus evolution after disruption of coronary atherosclerotic plaque.


METHODS
Thrombectomy materials (N=120) obtained from patients with acute myocardial infarction were histologically classified in three groups based on thrombus age: fresh (<1day), lytic (1-5days), or organized (>5days) thrombi; materials showing a heterogeneous composition were classified according to oldest part. Presence and cellular origin of MMPs (MMP-1, MMP-2, MMP-8, MMP-9, and MMP-14) and TIMPs (TIMP-1, TIMP-2, and TIMP-3) was evaluated with immunostains (double) and with polymerase chain reaction.


CONCLUSIONS
MMPs and TIMPs were present in all the thrombectomy samples. A distinct temporal change in extent and cellular origin of MMPs and TIMPs during thrombus evolution was observed. In the early (fresh and lytic) stages of thrombus, high numbers of neutrophilic granulocytes occupy the thrombus mass and produce large amounts of MMPs and TIMPs. However, with progression of thrombus evolution (organizing stage) and diminishment of neutrophil granulocytes, there is disappearance of MMP-8 and MMP-9, steep decline of MMP-1 and TIMP-2, and progressive decrease of TIMP-3. In contrast, intrathrombotic MMP-2 and MMP-14 are present at a constant high level during the entire process of thrombus evolution. These temporal changes indicate a complex time-dependent function of MMPs, which are largely granulocyte derived, in the healing process of thrombus after plaque disruption.
Department of Pathology, Academic Medical Center, University of Amsterdam, 1012WX Amsterdam, The Netherlands.
Xiaofei
X
Li
Department of Pathology, Academic Medical Center, University of Amsterdam, 1012WX Amsterdam, The Netherlands.
Onno J
OJ
de Boer
Department of Pathology, Academic Medical Center, University of Amsterdam, 1012WX Amsterdam, The Netherlands.
Hanneke
H
Ploegmaker
Department of Pathology, Academic Medical Center, University of Amsterdam, 1012WX Amsterdam, The Netherlands.
Peter
P
Teeling
Department of Pathology, Academic Medical Center, University of Amsterdam, 1012WX Amsterdam, The Netherlands.
Mat Jap
MJ
Daemen
Department of Cardiology, Academic Medical Center, University of Amsterdam, 1012WX Amsterdam, The Netherlands.
Robbert J
RJ
de Winter
Department of Pathology, Academic Medical Center, University of Amsterdam, 1012WX Amsterdam, The Netherlands. Electronic address: a.c.vanderwal@amc.uva.nl.
Allard C
AC
van der Wal
D001706:Biopsy; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D003328:Coronary Thrombosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D003331:Coronary Vessels / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D015971:Gene Expression Regulation, Enzymologic; D006098:Granulocytes / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D058226:Plaque, Atherosclerotic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017131:Thrombectomy; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases
Acute myocardial infarction; Atherosclerosis; Coronary artery; Granulocytes; Immunohistochemistry; Inflammation; Matrix metalloproteinase; Thrombosis