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

Abstract

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.

• Authors: Mesut Eren, Corrie A Painter, James B Atkinson, Paul J Declerck, Douglas E Vaughan
• Journal: Circulation (Circulation) Vol. 106 Issue 4 Pg. 491-6 (Jul 23 2002) ISSN: 1524-4539 [Electronic] United States
• PMID: 12135951 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Plasminogen Activator Inhibitor 1
• Protein C
• RNA, Messenger
• Plasminogen Activators

Topics

• Age Factors
• Animals
• Coronary Thrombosis (blood, etiology, pathology)
• Coronary Vessels (chemistry)
• Female
• Fibrosis
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Transgenic
• Myocardial Infarction (etiology, pathology)
• Plasminogen Activator Inhibitor 1 (genetics, immunology, metabolism)
• Plasminogen Activators (blood)
• Protein C (analysis)
• RNA, Messenger (biosynthesis)
• Tissue Distribution