Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: a potential factor predisposing to thrombosis and its persistence.
BACKGROUND
Inhibition of fibrinolysis attributable to elevated concentrations of plasminogen activator inhibitor type 1 (PAI-1) in blood is associated with insulin resistance, hyperinsulinemia, and type 2 diabetes mellitus. Because we have shown that insulin can stimulate PAI-1 synthesis in vivo and because accelerated vascular disease is common in such patients as well, we hypothesized that increased PAI-1, potentially predisposing to thrombosis, acute occlusion, and accelerating atherosclerosis because of thrombus-associated mitogens, would be present in excess in atheroma from type 2 diabetic subjects.


RESULTS
Samples acquired by directional coronary atherectomy from 25 patients with type 2 diabetes and 18 patients without diabetes were characterized qualitatively histologically for cellularity and by immunohistochemistry visually and qualitatively and by quantitative image analysis for assessment of urokinase-type plasminogen activator (u-PA) and PAI-1. Patients with and without diabetes were similar with respect to demographic features and the distribution and severity of coronary artery disease. Substantially more PAI-1 and substantially less u-PA were present in the atherectomy samples from subjects with diabetes.


CONCLUSIONS
The disproportionate elevation of PAI-1 compared with u-PA observed in atheromatous material extracted from vessels of diabetic subjects is consistent with increased gene expression of PAI-1 in vessels as well as the known increase of PAI-1 in blood, presumably reflecting increased synthesis. The increased PAI-1 detected in the atheroma may contribute in vivo to accelerated or persistent thrombosis underlying acute occlusion and to vasculopathy exacerbated by clot-associated mitogens in the vessel wall. Because the changes were observed to be associated with insulin resistance and type 2 diabetes mellitus, they may be modifiable by reduction of insulin resistance with insulin sensitizers and stringent control of hyperglycemia.
Sobel
B E
BE
Department of Medicine, The University of Vermont College of Medicine, Burlington 05401, USA. burton.sobel@vtmednet.org
Woodcock-Mitchell
J
J
Schneider
D J
DJ
Holt
R E
RE
Marutsuka
K
K
Gold
H
H
D000368:Aged; D000369:Aged, 80 and over; D001158:Arteries; D001161:Arteriosclerosis / Q000150:complications* / Q000378:metabolism / Q000601:surgery; D017073:Atherectomy; D003327:Coronary Disease / Q000150:complications* / Q000378:metabolism / Q000601:surgery; D003328:Coronary Thrombosis / Q000209:etiology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D012307:Risk Factors; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D014568:Urokinase-Type Plasminogen Activator