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

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.

• Authors: Katrin Schafer, Katja Müller, Anneke Hecke, Emmanuelle Mounier, Julia Goebel, David J Loskutoff, Stavros Konstantinides
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 23 Issue 11 Pg. 2097-103 (Nov 01 2003) ISSN: 1524-4636 [Electronic] United States
• PMID: 14512369 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apolipoproteins E
• Plasminogen Activator Inhibitor 1
• RNA

Topics

• Animals
• Apolipoproteins E (metabolism)
• Arteriosclerosis (complications, metabolism, pathology)
• Blood Platelets (metabolism)
• Carotid Artery Thrombosis (complications, metabolism, pathology)
• Gene Expression
• Immunohistochemistry
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Plasminogen Activator Inhibitor 1 (blood, genetics)
• RNA (analysis)
• Tunica Intima (metabolism, pathology)