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. METHODS AND 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.
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. METHODS AND 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.
Authors: L Maria Belalcazar; Christie M Ballantyne; Wei Lang; Steven M Haffner; Julia Rushing; Dawn C Schwenke; F Xavier Pi-Sunyer; Russell P Tracy Journal: Arterioscler Thromb Vasc Biol Date: 2011-04-21 Impact factor: 8.311
Authors: Omar Bayomy; Ajay D Rao; Rajesh Garg; Anand Vaidya; Alyssa R Kotin; Beata Reiber; Stephanie Nijmeijer; Marcelo F Di Carli; Michael Jerosch-Herold; Raymond Y Kwong; Gail K Adler Journal: Metab Syndr Relat Disord Date: 2017-05-15 Impact factor: 1.894
Authors: A K M Tarikuz Zaman; Satoshi Fujii; David J Schneider; Douglas J Taatjes; H Roger Lijnen; Burton E Sobel Journal: Histochem Cell Biol Date: 2007-06-19 Impact factor: 4.304
Authors: Frédéric Mouquet; François Cuilleret; Sophie Susen; Karine Sautière; Philippe Marboeuf; Pierre Vladimir Ennezat; Eugène McFadden; Pascal Pigny; Florence Richard; Bernadette Hennache; Marie Christine Vantyghem; Michel Bertrand; Jean Dallongeville; Brigitte Jude; Eric Van Belle Journal: Eur Heart J Date: 2009-01-22 Impact factor: 29.983