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Impact of Diabetes-Associated Lipoproteins on Generation of Fibrinolytic Regulators from Vascular Endothelial Cells

Diabetes Research Group, University of Manitoba (S.R., L.H., L.L., G.X.S.), and Rossmere Medical Clinic (H.L.), Winnipeg, Manitoba, Canada R3E 3P4

Address all correspondence and requests for reprints to: Garry X. Shen, M.D., Ph.D., Diabetes Research Group, University of Manitoba, 835-715 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 3P4. E-mail: gshen{at}ms.umanitoba.ca

Increased thrombotic tendency and decreased fibrinolytic activity have been frequently found in patients with diabetes mellitus (DM). Previous studies by our group indicated that nonenzymatically glycated low density lipoprotein (LDL) increased plasminogen activator inhibitor-1 (PAI-1) production and decreased the generation of tissue plasminogen activator (tPA) from cultured human umbilical vein endothelial cells (HUVEC). The present study demonstrates that plasma levels of PAI-1 or PAI-1/tPA were significantly increased in patients with type 1 (n = 10) and type 2 DM (n = 14) compared with those in healthy controls (n = 10; P < 0.05 or 0.01). LDL from patients with type 1 or type 2 DM, and very low density lipoprotein (VLDL) from patients with type 2 DM induced significantly greater increases in the release of PAI-1 and more profound reduction in tPA generation from HUVEC compared with corresponding lipoproteins from healthy controls (P < 0.05 or 0.01). HDL from diabetic patients did not significantly alter the generation of PAI-1 or tPA from endothelial cells (EC) compared with HDL from controls. Comparable effects of lipoproteins from DM patients on the generation of PAI-1 and tPA were found in human coronary artery EC. LDL and VLDL from patients with type 2 DM enhanced the activation of PAI-1 promoter (-1528/+55)/luciferase reporter gene transiently transfected in HUVEC (P < 0.01). The results of the present study suggest that LDL and VLDL from patients with DM reduce the generation of tPA and increase PAI-1 production through the activation of the PAI-1 promoter in vascular EC.

This work was supported by operating grants from the Canadian Diabetes Association in the memory of late Archibald Mitchell, the Canadian Institute of Health Research, the Health Sciences Centre Foundation, and the St. James Kiwanis Club (to G.X.S.).

Abbreviations: CAT, Chloramphenicol acetyltransferase; DM, diabetes mellitus; EC, endothelial cells; HbA_1c, hemoglobin A_1c; HCAEC, human coronary artery EC; HUVEC, human umbilical vein endothelial cells; LDL, low density lipoprotein; PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen activator; VLDL, very low density lipoprotein.

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