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

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Abstract
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 P P −/− 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.