Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice.
Epidemiological studies suggest that elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) predispose an individual to ischemic heart disease or promote plaque progression by inhibiting fibrinolysis. In the present study, loss of PAI-1 in apolipoprotein E (apoE)-deficient (apoE(-/-):PAI-1(-/-)) mice promoted the growth of advanced atherosclerotic plaques, which was due to enhanced extracellular matrix deposition. ApoE(-/-):PAI-1(-/-) plaques also exhibited collagen fiber disorganization and degradation. Immunostaining and bone marrow transplantation revealed that smooth muscle cells, not macrophages, primarily expressed PAI-1 in plaques. Thus, although PAI-1 may promote plaque growth because of its antifibrinolytic properties, the present study reveals a protective role for PAI-1 by limiting plaque growth and preventing abnormal matrix remodeling.
Luttun
Aernout
A
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
Lupu
Florea
F
Storkebaum
Erik
E
Hoylaerts
Marc F
MF
Moons
Lieve
L
Crawley
James
J
Bono
Françoise
F
Poole
A Robin
AR
Tipping
Peter
P
Herbert
Jean-Marc
JM
Collen
Désiré
D
Carmeliet
Peter
P
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism / Q000648:ultrastructure; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D005341:Fibrinolysin / Q000096:biosynthesis; D005342:Fibrinolysis; D005347:Fibroblasts / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D001057:Apolipoproteins E; D017395:Plasminogen Activator Inhibitor 1; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D002784:Cholesterol; D005341:Fibrinolysin