Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1
H. Sjoland et al., Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1, ART THROM V, 20(3), 2000, pp. 846-852
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.