Overexpression of tissue-type plasminogen activator in atherosclerotic human coronary arteries.
The plasminogen activator (PA)/plasmin system is involved in various pathological processes that are considered important features of atherogenesis and atherothrombosis. These include the proteolysis of fibrin deposits and extracellular matrix components as well as the induction of cell migration and mitogenesis. Tissue-type PA (TPA) is a key enzyme mediating plasminogen to plasmin conversion. TPA plasma concentrations are elevated in patients with advanced atherosclerosis and correlate with an increased risk for myocardial infarction and stroke. In this study, we have analysed the content and expression of TPA in human coronary arteries and their relation to the presence and severity of atherosclerotic lesions.


METHODS
Segments of coronary arteries obtained from heart explants (n = 15) were classified by the presence and types of atherosclerotic lesions. TPA was quantitatively determined in protein extracts of intimal and medial layers. In situ hybridization and immunohistochemical analyses were performed on serial sections of representative tissue specimens.


RESULTS
PA activity entirely attributable to the presence of active TPA was consistently detected in the protein extracts. Extractable TPA antigen and activity showed a significant graded increase in relation to the presence and severity of atherosclerotic lesions. The ratios of active over total TPA were increased several-fold in extracts of advanced lesions despite a concomitant threefold increase in TPA complexed to its inhibitor PA-1. In macroscopically normal arterial segments and in early lesions, TPA was expressed in the endothelium and in colocalization with vascular smooth muscle cells (VSMCs). In advanced plaques, TPA mRNA was mainly detected in the lateral regions of the fibrous caps in association with migrating VSMCs and in the vicinity of the core areas infiltrated by CD68-positive macrophages.


CONCLUSIONS
TPA content and expression is consistently increased in relation to the severity of the lesions in atherosclerotic coronary arteries. This may contribute to plaque destabilization and disruption. Conversely, the increased intramural TPA activity may counteract mural fibrin deposition.
Steins
M B
MB
Department of Internal Medicine, University of Münster, Germany.
Padró
T
T
Li
C X
CX
Mesters
R M
RM
Ostermann
H
H
Hammel
D
D
Scheld
H H
HH
Berdel
W E
WE
Kienast
J
J
D001158:Arteries / Q000378:metabolism; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D010960:Plasminogen Activators / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator