Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1.

Eren M, Painter CA, Atkinson JB, Declerck PJ, Vaughan DE
Circulation. 2002 106 (4): 491-6

PMID: 12135951 · DOI:10.1161/01.cir.0000023186.60090.fb

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.

METHODS AND 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.

MeSH Terms (17)

Age Factors Animals Coronary Thrombosis Coronary Vessels Female Fibrosis Humans Immunohistochemistry Male Mice Mice, Transgenic Myocardial Infarction Plasminogen Activator Inhibitor 1 Plasminogen Activators Protein C RNA, Messenger Tissue Distribution

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