Atherosclerosis Progression in LDL Receptor–Deficient and Apolipoprotein E–Deficient Mice Is Independent of Genetic Alterations in Plasminogen Activator Inhibitor-1

Abstract

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 (apoEϪ/Ϫ) and mice lacking the low density lipoprotein receptor (LDLRϪ/Ϫ) were crossbred with transgenic mice overexpressing PAI-1 (resulting in PAI-1 Tg ϩ /apoEϪ/Ϫ and PAI-1 Tg ϩ /LDLRϪ/Ϫ, respectively) or were crossbred with mice completely deficient in PAI-1 gene expression (resulting in PAI-1Ϫ/Ϫ/apoEϪ/Ϫ and PAI-1Ϫ/Ϫ/LDLRϪ/Ϫ, 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 apoEϪ/Ϫ than in comparable LDLRϪ/Ϫ mice. No significant differences in lesion size or histological appearance were observed among PAI-1Ϫ/Ϫ, PAI-1 Tg ϩ , or PAI-1 wild-type mice at any of the time points on either the apoEϪ/Ϫ or LDLRϪ/Ϫ 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 Ⅲ plasminogen activator inhibitor-1 Ⅲ apolipoprotein E Ⅲ low density lipoprotein receptors Ⅲ transgenic mice

Homozygosity for Factor V Leiden Leads to Enhanced Thrombosis and Atherosclerosis in Mice

“…Genotyping for FVL and ApoE was performed by polymerase chain reaction (PCR) analysis of tail DNA with the primers previously described. 13,14 After weaning, at 3 weeks of age, mice were fed standard chow (laboratory rodent diet No. 5001, TestDiet).…”

Reduction of Blood Pressure, Plasma Cholesterol, and Atherosclerosis by Elevated Endothelial Nitric Oxide

“…Male mice of 8 weeks were fed a Western type diet containing 15% (w/w) cacoa butter and 0.25% (w/w) cholesterol (diet W, Hope Farms, Woerden, The Netherlands) for 6 weeks, which leads to appreciable atherosclerosis (22)(23)(24). Animals were anesthetized using isoflurane, and in situ fixation was performed via the left ventricle of the heart using phosphate-buffered formalin (4%, v/v).…”

Serine Protease Inhibitor Serp-1 Strongly Impairs Atherosclerotic Lesion Formation and Induces a Stable Plaque Phenotype in ApoE −/− Mice

“…Comparison of the effects of Serp-1 to that of PAI-1 may thus hold a key to elucidation of the actual mechanism by which Serp-1 exerts its atheroprotective effect. Unfortunately, conflicting data on PAI-1 2,12,13 emphasize that the effects of modulation of serine protease activity are intricately dependent on the local protease milieu and the disease progression and leave unanswered to what extent antiinflammatory effects of Serp-1 may contribute to its beneficial effect as well. Other studies on the role of tPA and uPA in atherogenesis have shown that overexpression of uPA in carotid arteries in rabbits results in an acceleration of plaque growth, although no difference in plaque morphology was observed.…”

“…11 The precise relevance of these inhibitors to atherosclerosis is largely unclear. Thus, some researchers have found the serpin plasminogen activator inhibitor-1 (PAI-1) to have no effect on de novo atherogenesis in hypercholesterolemic mice, 12 whereas others have demonstrated PAI-1 deficiency to be atheroprotective in early atherosclerosis 2 and to accelerate plaque progression in advanced atherosclerosis. 13 Its effect in restenosis appears to be more clear-cut, as studies have demonstrated an exacerbating role for PAI-1 in neointima formation by promoting smooth muscle cell migration and proliferation.…”