Hypofibrinolysis associated with vasculopathy in non insulin dependent diabetes mellitus

Frade, L.J. García; Calle, Hermenegildo de la; Torrado, Mario; Lara, J I; Cuéllar, L; Avello, A. Garcia

doi:10.1016/0049-3848(90)90270-m

Cited by 68 publications

(34 citation statements)

References 21 publications

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“…6 " 8 In this study, we found that diabetic subjects without clinical evidence of ischemic heart disease had significantly higher PAI-1 activity and t-PA antigen levels compared with nondiabetic subjects and that diabetic survivors of myocardial infarction had higher PAI-1 activity and t-PA antigen levels than both control subjects and nondiabetic survivors of myocardial infarction.…”

Section: Discussionmentioning

confidence: 57%

Plasminogen activator inhibitor activity in diabetic and nondiabetic survivors of myocardial infarction.

Gray

Patterson

Yudkin

1993

Arterioscler Thromb

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Recent studies suggest that plasminogen activator inhibitor (PAI-1) may be a risk factor for recurrent myocardial infarction. We measured PAI-1 activity and antigen and tissue-type plasminogen activator (t-PA) antigen in 35 (20 nondiabetic and 15 diabetic) subjects with no clinical or electrocardiographic evidence of ischemic heart disease and in 74 (50 nondiabetic and 24 diabetic subjects) who had survived a myocardial infarction in the preceding 6-24 months. Levels of PAI-1 activity (18.7±5.6 versus 12.0±3.8 arbitrary units [AU] per milliliter,p=0.001) and t-PA antigen (7.0±1.9 versus 4.6±2.0 ng/mL,/»=0.001) were significantly higher in diabetic compared with nondiabetic control subjects. Survivors of myocardial infarction had higher levels of PAI-1 activity and antigen and t-PA antigen than control subjects, and the diabetic survivors had higher levels of PAI-1 activity (25.3±6.7 versus 20.1±7.1 AU/mL, p=0.004) and t-PA antigen (10.6±4.3 versus 8.4±3.3 ng/mL, p=0.03) than the nondiabetic survivors. No difference in PAI-1 antigen levels was found between the diabetic subjects and either the nondiabetic control subjects or survivors of myocardial infarction. After venous occlusion in control subjects, there was a significant increase in PAI-1 antigen (mean 26.7%, range 14.1-58.1% in nondiabetics and mean 25.2%, range 6.2-39.7% in diabetics) and t-PA antigen (mean 78.3%, range 13.6-186.2% for nondiabetic and mean 40.7%, range 17.5-76.2% for diabetic subjects), but in the survivors of myocardial infarction, no significant effect of venous occlusion was observed. These results suggest that diabetic subjects have higher PAI-1 activity levels than nondiabetic subjects both after acute myocardial infarction and in the absence of ischemic heart disease. The similar levels of PAI-1 antigen between the diabetic and nondiabetic subjects suggest that increased levels of t-PA-PAI-1 complexes cannot explain the increase in t-PA antigen in diabetic subjects. (Arteriosclerosis and Thrombosis 1993;13:415-420) KEY WORDS • plasminogen activator inhibitor-1 • diabetes • myocardial infarction T he cause of the high morbidity and mortality from ischemic heart disease and myocardial infarction in diabetic subjects 1 -2 remains unclear. The recent development of assays for specific components of the fibrinolytic system has led to renewed interest in the potential role of the fibrinolytic system in coronary artery disease and myocardial infarction. Recent studies have shown reduced fibrinolytic activity, largely due to elevated plasminogen activator inhibitor (PAI-1) activity, in various subgroups with an increased risk of coronary artery disease, including obese subjects, 3 patients with hypertension, 4 patients with angina pectoris, 5 and diabetic subjects without coronary artery disease.6 " 8 Elevated PAI-1 activity levels have also been demonstrated in young survivors of myocardial infarction 9 and have been shown to predispose to reinfarction in this group.

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Section: Discussionmentioning

confidence: 57%

Plasminogen activator inhibitor activity in diabetic and nondiabetic survivors of myocardial infarction.

Gray

Patterson

Yudkin

1993

Arterioscler Thromb

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“…The release of fibrinolytic activity from the vascular wall responding to temporary occlusion was impaired in patients with DM. 1,2 The production of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in vascular endothelial cells (ECs) is modulated by thrombin, 3 glucose, 4 proinsulin, 5 growth factors, 6 and several types of plasma lipoproteins. [7][8][9][10][11][12][13] Elevated levels of glycated LDL were detected in the plasma of patients with DM.…”

mentioning

confidence: 99%

Impact of Antioxidants and HDL on Glycated LDL–Induced Generation of Fibrinolytic Regulators From Vascular Endothelial Cells

Ren

Shen

2000

ATVB

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Abstract-Hyperglycemia and dyslipoproteinemia are biochemical markers of diabetes mellitus (DM). Elevated levels of plasminogen activator inhibitor-1 (PAI-1) with and without reduction of tissue plasminogen activator (tPA) in plasma have been frequently found in patients with DM. Our previous studies indicated that glycation enhances low density lipoprotein (LDL)-induced production of PAI-1 and further decreases tPA generation in vascular endothelial cells (ECs). The present study demonstrated that treatment with antioxidants, butylated hydroxytoluene or vitamin E, blocked native LDL-and glycated LDL-induced changes in PAI-1 and tPA generation in ECs. Native or glycated high density lipoprotein (HDL) did not significantly alter tPA generation in ECs. Glycated but not native HDL (Ն100 g/mL) moderately increased PAI-1 release from ECs. Cotreatment with native or glycated HDL inhibited LDL-induced or glycated LDL-induced changes in PAI-1 and tPA generation in ECs. The abundance of conjugated dienes was increased in glycated or EC-modified LDL. Treatment with butylated hydroxytoluene, vitamin E, or HDL reduced the abundance of conjugated dienes in glycated or EC-modified LDL. The effects of antioxidants and HDL on LDL-induced or its glycated LDL-induced changes in the generation of PAI-1 and tPA were also found in cultured human coronary artery ECs. The findings of the present study suggest that antioxidants and HDL may attenuate native LDL-or glycated LDL-induced changes in the generation of fibrinolytic regulators from vascular ECs, which possibly results from their inhibition on the lipid peroxidation of LDL particles. Treatment with antioxidants or hypolipidemic agents potentially improves fibrinolytic activity and reduces thrombotic tendencies in patients with DM. Key Words: LDL Ⅲ glycation Ⅲ antioxidants Ⅲ HDL Ⅲ plasminogen activator inhibitor-1 H yperglycemia and dyslipoproteinemia, 2 major biochemical markers in diabetes mellitus (DM), have been implicated in the development of cardiovascular complications in patients with DM. Intravascular thrombosis plays a critical role in the development of ischemic events with and without the presence of atherosclerotic lesions. The formation of thrombus in the vasculature mainly depends on the balance between coagulation and fibrinolysis. The release of fibrinolytic activity from the vascular wall responding to temporary occlusion was impaired in patients with DM. 1,2 The production of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in vascular endothelial cells (ECs) is modulated by thrombin, 3 glucose, 4 proinsulin, 5 growth factors, 6 and several types of plasma lipoproteins. [7][8][9][10][11][12][13] Elevated levels of glycated LDL were detected in the plasma of patients with DM. 14,15 Previous studies by our group demonstrated that glycation enhanced LDL-induced overproduction of PAI-1 and further reduced the generation of tPA from cultured vascular ECs. 13 Glycation increases the oxidative stress of lipoproteins. 16 Treatment with...

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“…Attenuated fibrinolytic activity or reduced fibrinolytic response to ischemic stimulus has been found in diabetic subjects. 2,7 Vascular ECs synthesize both PAI-1 and tPA. The generation of PAI-1 or tPA from ECs is regulated by a variety of biological agonists, including plasma lipoproteins.…”

mentioning

confidence: 99%

“…1 Disorders in lipid metabolism, coagulation, and fibrinolysis have been implicated in the development of diabetic vascular complications. 2 It is generally accepted that hemostasis is determined by a balance between coagulation and fibrinolysis. Imbalance between the two antagonistic systems may result in thrombosis or hemorrhage.…”

mentioning

confidence: 99%

Influence of Glycation on LDL-Induced Generation of Fibrinolytic Regulators in Vascular Endothelial Cells

Zhang

Ren

Sun

et al. 1998

ATVB

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Abstract-Hyperglycemia and dyslipidemia are two biochemical markers of diabetes mellitus. Increased incidence of cardiovascular disease and impaired fibrinolytic activity have been found in diabetic subjects. Previous studies have demonstrated that low density lipoproteins (LDLs) stimulate the production of plasminogen activator inhibitor-1 (PAI-1) and reduce the generation of tissue plasminogen activator (tPA) in vascular endothelial cells (ECs). The present study investigated the effect of glycated LDL on the production of PAI-1 and tPA in cultured human umbilical vein ECs (HUVECs). Glycation increased the abundance of glucitollysine and conjugated dienes in LDL and amplified the overproduction of PAI-1 and the reduction in tPA generation from HUVECs induced by LDL. The steady-state levels of PAI-1 mRNA in glycated LDL-treated ECs were significantly higher than those in native LDL-treated cells. Actinomycin D blocked the increase in PAI-1 generation induced by glycated LDL. Glycated LDL did not significantly reduce the levels of tPA mRNA but attenuated de novo synthesis of tPA in ECs. Treatment with 25 mmol/L aminoguanidine, an antioxidant and inhibitor of the formation of advanced glycation end products, during glycation normalized glycated LDL-induced generation of PAI-1 and tPA in ECs. The results of the present study indicate that glycation enhances the production of PAI-1 and attenuates tPA synthesis in ECs induced by LDL, which may contribute to the increased incidence of cardiovascular complications in diabetes. Formation of advanced glycation end products or peroxidation may be involved in glycated LDL-induced alterations in the generation of fibrinolytic regulators from ECs.

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Hypofibrinolysis associated with vasculopathy in non insulin dependent diabetes mellitus

Cited by 68 publications

References 21 publications

Plasminogen activator inhibitor activity in diabetic and nondiabetic survivors of myocardial infarction.

Plasminogen activator inhibitor activity in diabetic and nondiabetic survivors of myocardial infarction.

Impact of Antioxidants and HDL on Glycated LDL–Induced Generation of Fibrinolytic Regulators From Vascular Endothelial Cells

Influence of Glycation on LDL-Induced Generation of Fibrinolytic Regulators in Vascular Endothelial Cells

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