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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:2097.)
© 2003 American Heart Association, Inc.

Thrombosis

Enhanced Thrombosis in Atherosclerosis-Prone Mice Is Associated With Increased Arterial Expression of Plasminogen Activator Inhibitor-1

Katrin Schäfer; Katja Müller; Anneke Hecke; Emmanuelle Mounier; Julia Goebel; David J. Loskutoff; Stavros Konstantinides

From Department of Cardiology and Pulmonary Medicine (K.S., K.M., A.H., E.M., J.G., S.K.), Georg August University of Goettingen, Germany, and Department of Cell Biology (D.J.L.), Division of Vascular Biology, Scripps Research Institute, La Jolla, Calif.

Correspondence to Stavros Konstantinides, MD, Department of Cardiology and Pulmonary Medicine, University of Goettingen, Robert Koch Strasse 40, D-37075 Goettingen, Germany. E-mail skonstan{at}med.uni-goettingen.de

Objectives— This study was undertaken to investigate the origin and pathophysiological importance of plasminogen activator inhibitor (PAI-1) in atherosclerosis.

Methods and Results— We used the ferric chloride model to induce carotid artery injury in apolipoprotein E knockout (apoE^-/-) and wild-type (WT) mice. ApoE^-/- mice fed high-fat diet for 4 months developed severe hypercholesterolemia and had significantly elevated plasma PAI-1 levels (2.3±0.3 versus 0.6±0.1 ng/mL in WT mice; P<0.05). These mice exhibited a prothrombotic phenotype with shortened times to thrombotic arterial occlusion (8.6 versus 11.5 minutes; P<0.001) and reduced recanalization rates (12% versus 51%; P<0.0001) compared with WT mice. In situ hybridization, reverse transcriptase–polymerase chain reaction, and immunohistochemistry showed a significantly upregulated PAI-1 expression in P-selectin–positive (activated) endothelial cells lining normal-appearing arterial segments and within the advanced atherosclerotic lesions of apoE^-/- mice. No significant upregulation of PAI-1 expression was found in the other organs studied, and only trace amounts of PAI-1 mRNA were detected in murine platelets. Importantly, deletion of the PAI-1 gene reversed the prothrombotic tendency and reduced neointimal growth after injury in apoE^-/- mice despite the persistence of excessive hypercholesterolemia.

Conclusions— These results suggest that increased vascular expression of PAI-1 may contribute to the elevated circulating levels of the inhibitor and be responsible, at least in part, for the prothrombotic phenotype in apoE^-/- mice.

Key Words: atherosclerosis • thrombosis • plasminogen activator inhibitor • arteries • mouse models

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