Enhanced thrombosis in atherosclerosis-prone mice is associated with increased arterial expression of plasminogen activator inhibitor-1.
OBJECTIVE
This study was undertaken to investigate the origin and pathophysiological importance of plasminogen activator inhibitor (PAI-1) in atherosclerosis.


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.
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001161:Arteriosclerosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism; D002341:Carotid Artery Thrombosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000235:genetics; D012313:RNA / Q000032:analysis; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
D001057:Apolipoproteins E; D017395:Plasminogen Activator Inhibitor 1; D012313:RNA