Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1

Impaired fibrinolysis has been linked to atherosclerosis in a number of exp erimental and clinical studies. Plasminogen activator inhibitor type 1 (PAI -I) is the primary inhibitor of plasminogen activation and has been propose d to promote atherosclerosis by facilitating fibrin deposition within devel oping lesions. We examined the contribution of PAI-1 to disease progression in 2 established mouse models of atherosclerosis. Mice lacking apolipoprot ein E (apoE -/-) and mice lacking the low density lipoprotein receptor (LDL R-/-) were crossbred with transgenic mice overexpressing PAI-1 (resulting i n PAI-1 Tg(+)/apoE-/- and PAI-1 Tg(+)/LDLR-/-, respectively) or were crossb red with mice completely deficient in PAI-1 gene expression (resulting in P AI-I-/-/apaE-/- and PAT-I -/-/LDLR-/-, respectively). All animals were plac ed on a western diet (21% Eat and 0.15% cholesterol) at 4 weeks of age and analyzed for the extent of atherosclerosis after an additional 6, 15, or 30 weeks. Intimal and medial areas were determined by computer-assisted morph ometric analysis of standardized microscopic sections from the base of the aorta. Atherosclerotic lesions were also characterized by histochemical ana lyses with the use of markers for smooth muscle cells, macrophages, and fib rin deposition. Typical atherosclerotic lesions were observed in all experi mental animals, with greater severity at the later time points and generall y more extensive lesions in apoE-/- than in comparable LDLR-/mice. No signi ficant differences in lesion size or histological appearance were observed among PAI-I-/-, PAI-I Tg(+), or PAI-1 wild-type mice at any of the time poi nts on either the apoE-/- or LDLR-/- genetic background. We conclude that g enetic modification of PAI-1 expression does not significantly alter the pr ogression of atherosclerosis in either of these well-established mouse mode ls. These results suggest that fibrinolytic balance (as well as the potenti al contribution of PAI-1 to the regulation of cell migration) plays only a limited role in the pathogenesis of the simple atherosclerotic lesions obse rved in the mouse.