Overexpression of matrix metalloproteinase-9 promotes intravascular thrombus formation in porcine coronary arteries in vivo.
OBJECTIVE
Matrix metalloproteinases (MMPs) cause extracellular matrix degradation and may be involved in the rupture of atherosclerotic plaques by degrading fibrous cap, resulting in the intravascular thrombus formation. Here we examined whether local overexpression of MMP-9 alters the characteristics of arteriosclerotic vascular lesions and promotes thrombosis after balloon injury in porcine coronary arteries in vivo.


RESULTS
Balloon angioplasty was performed in the left coronary arteries followed by injection of adenovirus vector solution encoding either MMP-9 or beta-galactosidase (beta-gal) gene into the injured coronary arteries. Three weeks after the gene transfer, histological examination demonstrated that macroscopic intravascular thrombus formation was noted at the MMP-9-transfected site but not at the beta-gal-transfected site. Microscopic intramural thrombus area was significantly larger at the MMP-9-transfected site as compared to the beta-gal-transfected site. Co-transfection of tissue inhibitor of metalloproteinase-1 (TIMP-1) with MMP-9 prevented the intravascular thrombus formation in vivo. Western blot analysis revealed the reduced expression of intact tissue factor pathway inhibitor-1 and the increased tissue factor (TF) expression at the MMP-9-transfected sites.


CONCLUSIONS
These results provide the first in vivo evidence that overexpression of MMP-9 promotes intravascular thrombus formation after balloon injury due in part to the activation of TF-mediated coagulation cascade.
Morishige
Kunio
K
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Shimokawa
Hiroaki
H
Matsumoto
Yasuharu
Y
Eto
Yasuhiro
Y
Uwatoku
Toyokazu
T
Abe
Kohtaro
K
Sueishi
Katsuo
K
Takeshita
Akira
A
D000256:Adenoviridae / Q000235:genetics; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D003324:Coronary Artery Disease / Q000150:complications / Q000628:therapy; D003328:Coronary Thrombosis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D005822:Genetic Vectors; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013552:Swine; D013925:Thromboplastin / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000502:physiology; D014162:Transfection
D008074:Lipoproteins; D019715:Tissue Inhibitor of Metalloproteinase-1; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D020780:Matrix Metalloproteinase 9