on July 1, 2002
Published online before print July 1, 2002, doi: 10.1161/01.CIR.0000023186.60090.FB
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Submitted on March 21, 2002
From the Division of Cardiovascular Medicine (M.E., C.A.P., D.E.V.) and Department of Pathology (J.B.A.), Vanderbilt University Medical Center, Nashville, Tenn, and Laboratory for Pharmaceutical Biology (P.J.D.), Katholieke Universiteit, Leuven, Belgium. * To whom correspondence should be addressed. E-mail: doug.vaughan{at}mcmail.vanderbilt.edu.
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.
Revised on May 9, 2002
Accepted on May 9, 2002
Age-Dependent Spontaneous Coronary Arterial Thrombosis in Transgenic Mice That Express a Stable Form of Human Plasminogen Activator Inhibitor-1
Mesut Eren PhD,
Key words: thrombus • coronary disease • myocardial infarction • plasminogen activators • fibrinolysis
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