Diabetes mellitus induces decreased plasma fibrinolytic activity and increased tissue synthesis of plasminogen activator inhibitor-1 (PAI-1) in the rat

Abstract

In diabetes, plasma fibrinolytic activity is decreased while plasma plasminogen activator inhibitor-1 (PAI-1) is increased. Both liver and adipose tissue can synthesize and release PAI-1, but PAI-1 synthesis in these tissues has not been investigated in diabetes. Furthermore, little is known about PAI-1 localization in arterial wall cells of diabetic animals. The aim of this study was to determine the effect of chronic hyperglycemia on plasma fibrinolysis and plasma PAI-1 levels and on liver, adipose tissue and arterial wall PAI-1 content in the rat.

We compared plasma fibrinolytic activity (lysis of fibrin plates) and plasma PAI-1 activity (chromogenic assay) in 10 Sprague Dowley 90% pancreatectomized rats (a model of diabetes characterized by normal fasting insulin and the absence of obesity, therefore closely resembling lean type 2 diabetes) and in 15 sham-operated rats. Furthermore, we measured PAI-1-related fluorescence, by immunofluorescent staining and Laser Scanning Confocal Microscopy, in liver, adipose tissue and aortic wall in diabetic and control animals.

In the diabetic animals plasma fibrinolytic activity was reduced (lysis areas = 163 ± 23 vs 308 ± 21 mm², P< 0.001), while plasma PAI-1 activity was increased (4.61 ± 2.01 AU vs 0.70 ± 0.59 AU, P< 0.02). PAI-1 related fluorescence was increased in the liver (754 ± 25 vs 299 ± 14 AFU, P< 0.0001), in the adipose tissue (721 ± 32 vs 248 ± 14 AFU, P< 0.001) and in the aorta wall (339 ± 18 vs 274 ± 9 AFU,P < 0.005) of the diabetic animals.

These data provide evidence that in diabetes mellitus hyperglycemia is associated with increased PAI-1 content in the liver, adipose tissue and in the arterial wall. This suggests that in diabetes the liver and adipose tissue can be important sources for increased plasma PAI-1 and local fibrinolysis can be affected by increased PAI-1 levels in the arterial wall.