Overexpression of urokinase by plaque macrophages causes histological features of plaque rupture and increases vascular matrix metalloproteinase activity in aged apolipoprotein e-null mice.
BACKGROUND
The mechanisms of atherosclerotic plaque rupture are poorly understood. Urokinase-type plasminogen activator (uPA) is expressed at elevated levels by macrophages in advanced human plaques. Patients with evidence of increased plasminogen activation have an elevated risk of major cardiovascular events. We used atherosclerotic mice to test the hypothesis that increased macrophage uPA expression in advanced plaques would cause histological features similar to those in ruptured human plaques.


RESULTS
Bone marrow from transgenic mice with increased macrophage uPA expression or nontransgenic controls (all apolipoprotein E-null [Apoe(-/-)]) was transplanted into 35-week-old Apoe(-/-) recipients, and innominate lesions and aortas were examined 8 to 13 weeks later. Donor macrophages accumulated in innominate lesions adjacent to plaque caps and in aortas, increasing uPA expression at both sites. Recipients of uPA-overexpressing macrophages had an increased prevalence of intraplaque hemorrhage (61% versus 13%; P=0.002) as well as increased lesion fibrin staining and fibrous cap disruption (P=0.06 for both). Transplantation of uPA-overexpressing macrophages increased aortic matrix metalloproteinase activity (40%; P=0.02). This increase was independent of matrix metalloproteinase-9.


CONCLUSIONS
In advanced plaques of Apoe(-/-) mice, macrophage uPA overexpression causes intraplaque hemorrhage and fibrous cap disruption, features associated with human plaque rupture. uPA overexpression also increases vascular matrix metalloproteinase activity. These data provide a mechanism that connects macrophage uPA expression, matrix metalloproteinase activity, and plaque rupture features in mice. The data also suggest that elevated plaque plasminogen activator expression and plasminogen activation in humans may be causally linked to plaque rupture and cardiovascular events.
Hu
Jie Hong
JH
Department of Medicine, University of Washington School of Medicine, Seattle 98159-7710, USA.
Du
Liang
L
Chu
Talyn
T
Otsuka
Goro
G
Dronadula
Nagadhara
N
Jaffe
Mia
M
Gill
Sean E
SE
Parks
William C
WC
Dichek
David A
DA
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D001853:Bone Marrow / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D016122:Brachiocephalic Trunk / Q000201:enzymology / Q000502:physiology; D002318:Cardiovascular Diseases / Q000453:epidemiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006410:Hematopoiesis; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010958:Plasminogen / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
D000943:Antigens, Differentiation; D001057:Apolipoproteins E; C036763:monocyte-macrophage differentiation antigen; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases