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

Mesut Eren, Corrie A. Painter, James B. Atkinson, Paul J. Declerck, Douglas E. Vaughan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

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 PA1-1 are associated with age-dependent coronary arterial thrombosis in mice transgenic for human PA1-1. 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 PA1-1 excess contributes to the development of coronary arterial thrombosis.

Original languageEnglish (US)
Pages (from-to)491-496
Number of pages6
JournalCirculation
Volume106
Issue number4
DOIs
StatePublished - Jul 23 2002

Keywords

  • Coronary disease
  • Fibrinolysis
  • Myocardial infarction
  • Plasminogen activators
  • Thrombus

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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