Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1.
BACKGROUND
Plasminogen activator inhibitor-1 (PAI-1) regulates fibrinolysis and has been reported to be an independent risk factor for ischemic cardiovascular events. This study describes the age-dependent development of spontaneous coronary arterial thrombi that are associated with evidence of subendocardial myocardial infarction in mice transgenic for human PAI-1.


RESULTS
We generated two independent transgenic mice founder lines that express a stable variant of active human PAI-1 under control of the murine preproendothelin-1 (mPPET-1) promoter. Backcrossed homozygous transgenic animals from founder line I had plasma PAI-1 levels of 23+/-12 ng/mL. PAI-1 transgenic animals younger than 4 months do not exhibit any evidence of arterial or venous thrombosis. Ninety percent of transgenic animals (n=10) older than 6 months developed spontaneous occlusions of typically multiple, penetrating coronary arteries, with histological evidence of subendocardial infarction identified in 50% of animals.


CONCLUSIONS
This study shows that chronically elevated levels of PAI-1 are associated with age-dependent coronary arterial thrombosis in mice transgenic for human PAI-1. This is the first study of a murine model of coronary thrombosis that occurs in the absence of severe hypercholesterolemia or multiple genetic manipulations. These findings provide new evidence to support the hypothesis that PAI-1 excess contributes to the development of coronary arterial thrombosis.
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn 37232-6300, USA.
Mesut
M
Eren
Corrie A
CA
Painter
James B
JB
Atkinson
Paul J
PJ
Declerck
Douglas E
DE
Vaughan
D000367:Age Factors; D000818:Animals; D003328:Coronary Thrombosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D003331:Coronary Vessels / Q000737:chemistry; D005260:Female; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D010960:Plasminogen Activators / Q000097:blood; D011486:Protein C / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D014018:Tissue Distribution
D017395:Plasminogen Activator Inhibitor 1; D011486:Protein C; D012333:RNA, Messenger; D010960:Plasminogen Activators