© 2000 American Heart Association, Inc.
Thrombosis |
Atherosclerosis Progression in LDL Receptor–Deficient and Apolipoprotein E–Deficient Mice Is Independent of Genetic Alterations in Plasminogen Activator Inhibitor-1
From the Divisions of Cardiology (H.S., D.T.E., E.G.N.) and Molecular Medicine and Genetics (D. Ginsburg), Department of Internal Medicine, and the Department of Human Genetics (D. Ginsburg) and Howard Hughes Medical Institute (R.W., D. Ginsburg), University of Michigan Medical Center, Ann Arbor, and Cardiovascular Therapeutics (D. Gordon), Parke-Davis Pharmaceutical Research, Ann Arbor, Mich.
Correspondence to David Ginsburg, MD, Department of Human Genetics, Howard Hughes Medical Institute, University of Michigan Medical Center, 4520 MSRB I, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0644. E-mail ginsburg{at}umich.edu
Abstract—Impaired fibrinolysis has been linked to atherosclerosis in a number of experimental and clinical studies. Plasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of plasminogen activation and has been proposed to promote atherosclerosis by facilitating fibrin deposition within developing lesions. We examined the contribution of PAI-1 to disease progression in 2 established mouse models of atherosclerosis. Mice lacking apolipoprotein E (apoE-/-) and mice lacking the low density lipoprotein receptor (LDLR-/-) were crossbred with transgenic mice overexpressing PAI-1 (resulting in PAI-1 Tg+/apoE-/- and PAI-1 Tg+/LDLR-/-, respectively) or were crossbred with mice completely deficient in PAI-1 gene expression (resulting in PAI-1-/-/apoE-/- and PAI-1-/-/LDLR-/-, respectively). All animals were placed on a western diet (21% fat 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 morphometric analysis of standardized microscopic sections from the base of the aorta. Atherosclerotic lesions were also characterized by histochemical analyses with the use of markers for smooth muscle cells, macrophages, and fibrin deposition. Typical atherosclerotic lesions were observed in all experimental animals, with greater severity at the later time points and generally more extensive lesions in apoE-/- than in comparable LDLR-/- mice. No significant differences in lesion size or histological appearance were observed among PAI-1-/-, PAI-1 Tg+, or PAI-1 wild-type mice at any of the time points on either the apoE-/- or LDLR-/- genetic background. We conclude that genetic modification of PAI-1 expression does not significantly alter the progression of atherosclerosis in either of these well-established mouse models. These results suggest that fibrinolytic balance (as well as the potential contribution of PAI-1 to the regulation of cell migration) plays only a limited role in the pathogenesis of the simple atherosclerotic lesions observed in the mouse.
Key Words: atherosclerosis • plasminogen activator inhibitor-1 • apolipoprotein E • low density lipoprotein receptors • transgenic mice
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