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. 2003 Nov 1;23(11):2097-103.
doi: 10.1161/01.ATV.0000097766.36623.DF. Epub 2003 Sep 25.

Enhanced thrombosis in atherosclerosis-prone mice is associated with increased arterial expression of plasminogen activator inhibitor-1

Katrin Schafer  1 , Katja Müller, Anneke Hecke, Emmanuelle Mounier, Julia Goebel, David J Loskutoff, Stavros Konstantinides
Affiliations

Enhanced thrombosis in atherosclerosis-prone mice is associated with increased arterial expression of plasminogen activator inhibitor-1

Katrin Schafer et al. Arterioscler Thromb Vasc Biol. .

Abstract

Objective: 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.

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