Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states.

Schneider, David J.; Sobel, Burton E.

doi:10.1073/pnas.88.22.9959

Cited by 161 publications

(95 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The production of tPA was not reduced by hyperinsulinemia, indicating that the increased synthesis and release of PAI-1 was responsible for the impaired fibrinolytic response. These insulin effects are in line with laboratory studies demonstrating that both insulin and proinsulin can augment PAI-1 expression in endothelial cells (22), vascular smooth muscle cells (23), and hepatocytes (24) in vitro. In addition, even in subjects with normal glucose tolerance, elevated levels of fasting insulin are associated with increased circulating PAI-1 levels (6), providing further evidence for a link between hyperinsulinemia and impaired fibrinolysis.…”

Section: Discussionsupporting

confidence: 68%

Hyperglycemia Stimulates Coagulation, Whereas Hyperinsulinemia Impairs Fibrinolysis in Healthy Humans

et al. 2006

View full text Add to dashboard Cite

Type 2 diabetes and insulin resistance syndromes are associated with an increased risk for cardiovascular and thrombotic complications. A disturbed balance between coagulation and fibrinolysis has been implicated in the pathogenesis hereof. To determine the selective effects of hyperglycemia and hyperinsulinemia on coagulation and fibrinolysis, six healthy humans were studied on four occasions for 6 h: 1) lower insulinemic-euglycemic clamp, 2) lower insulinemic-hyperglycemic clamp, 3) hyperinsulinemic-euglycemic clamp, and 4) hyperinsulinemic-hyperglycemic clamp. In the hyperglycemic clamps, target levels of plasma glucose were 12 versus 5 mmol/l in the normoglycemic clamps. In the hyperinsulinemic clamps, target plasma insulin levels were 400 versus 100 pmol/l in the lower insulinemic clamps. Hyperglycemia exerted a procoagulant effect irrespective of insulin levels, as reflected by mean twofold rises in thrombin-antithrombin complexes and soluble tissue factor, whereas hyperinsulinemia inhibited fibrinolysis irrespective of glucose levels, as reflected by a decrease in plasminogen activator activity levels due to a mean 2.5-fold rise in plasminogen activator inhibitor type 1. The differential effects of hyperglycemia and hyperinsulinemia suggest that patients with hyperglycemia due to insulin resistance are especially susceptible to thrombotic events by a concurrent insulin-driven impairment of fibrinolysis and a glucose-driven activation of coagulation.

show abstract

Section: Discussionsupporting

confidence: 68%

Hyperglycemia Stimulates Coagulation, Whereas Hyperinsulinemia Impairs Fibrinolysis in Healthy Humans

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Plasma PAI-1 activity was measured as previously reported. 19) All assays were performed in duplicate and the intra-and interassay variability was less than 10%. Statistics: Data are expressed as the mean±SD and were compared using oneway analysis of variance if normally distributed.…”

Section: Vol 43 Nomentioning

confidence: 99%

Relationships between Brachial Artery Flow Mediated Dilation and Carotid Artery Intima-Media Thickness in Patients with Suspected Coronary Artery Disease.

et al. 2002

View full text Add to dashboard Cite

SUMMARYThe correlation of peripheral endothelial dysfunction and intima-media thickness (IMT) in patients with suspected coronary artery disease (CAD) has been unclear. Inflammation and thrombosis may play a role at early stages of atherosclerosis. Thus, early atherosclerosis was noninvasively examined morphologically by IMT of carotid arteries, and functionally by flow mediated dilation (FMD) of brachial arteries in patients who were suspected of CAD and had undergone coronary angiography. Plasma antigen levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6, representative atherogenic cytokines, tissue factor (TF) and tissue factor pathway inhibitor (TFPI), markers of coagulation, and plasma activity level of plasminogen activator inhibitor type-1 (PAI-1), a marker of defective fibrinolysis, were measured. Patients with coronary atherosclerosis in one or more vessels with lesion ≥50% had significantly reduced FMD compared with those with angiographically normal coronary arteries. Carotid artery IMT increased significantly only in patients with advanced coronary atherosclerosis in one or more vessels with lesion ≥90%. Plasma antigen levels of IL-6 were significantly increased in patients with reduced FMD (<5%) compared to those in patients with FMD between 10 and 15%. Plasma antigen levels of TF, total and free TFPI, and PAI-1 activity tended to increase with a reduction in FMD. Thus, (1) FMD was reduced at early stages of CAD while IMT was increased in advanced CAD, and (2) inflammation and thrombosis may play a role in the early stages of the atherosclerotic process. (Jpn Heart J 2002; 43: 117-125)

show abstract

“…Northern blotting was performed as previously described with 10 g RNA. 12 inserted into the unique KpnI site of the promoter-less luciferase reporter plasmid pGL3-Basic (Promega), and referred to as PAI-LUC 1313. A 927-bp XhoI fragment (from Ϫ853 to ϩ74 in human PAI-1 DNA) was inserted into the XhoI site of pGL3-Basic and referred to as PAI-LUC 853.…”

Section: Cell Culturementioning

confidence: 99%

Identification and Localization of a Fatty Acid Response Region in the Human Plasminogen Activator Inhibitor-1 Gene

Chen

Billadello

Schneider

2000

ATVB

View full text Add to dashboard Cite

Abstract-The increased expression of plasminogen activator inhibitor type-1 (PAI-1) is associated with increased concentrations of fatty acids in blood and may accelerate atherogenesis in diabetes. The present study was designed to define mechanisms by which nonesterified (free) fatty acids (FFAs) augment the expression of PAI- Key Words: Diabetes mellitus Ⅲ PAI-1 Ⅲ free fatty acids Ⅲ Sp1 P lasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of plasminogen activators, is increased in blood in patients with diabetes mellitus. 1 Altered lipid metabolism is associated with increased concentrations of triglycerides and nonesterified (free) fatty acids (FFAs) in these subjects. 2 We have found that the infusion of glucose and emulsified triglycerides (in combination with heparin to increase FFA concentrations) into healthy human subjects increases the concentration of PAI-1 in blood. 3 Further, the exposure of cells to triglycerides increases elaboration of PAI-1 protein secondary to increased transcription. 4 -6 In previous work, we found that the effect of triglycerides on expression of PAI-1 appears to be mediated, at least in part, by their constituents: FFAs. 7 Both FFAs and their metabolites, particularly long-chain acyl-CoA, have been shown to regulate the expression of genes through binding to or modification of transcription factors. 8 -11 We postulated that the induction of PAI-1 by FFAs is secondary to a direct or an indirect effect of FFAs on the expression and/or activation of a transcription factor or factors that bind to a cis-acting element in the 5Ј flanking region of the PAI-1 gene. The present study was designed to identify the cis-acting element or elements. Methods Cell CultureHuman hepatoma (HepG2) cells were obtained from American Type Culture Collection and grown in minimal essential media (MEM; GIBCO BRL) with 10% NuSerum (GIBCO BRL). Experiments were performed in DMEM with Ham's nutrient mixture F12 (DME-F12; GIBCO BRL).The sodium salts of FFAs (Sigma Chemical Co) were dissolved in water at 37°C and added dropwise to 1% fatty acid-free bovine serum albumin (FAF-BSA; Sigma Chemical Co) in DME-F12. We determined that 3% BSA in DME-F12 contains 0.45 mmol/L FFAs (Wako NEFA C kits; Biochemical Diagnostics). All solutions were adjusted to pH 7.4 and filtered through a 0.22-m filter.Eighty percent confluent HepG2 cells were preincubated in serum-free DME-F12 for 4 to 8 hours. Subsequently, cells were exposed to DME-F12 with FAF-BSA, DME-F12 with FAF-BSA to which selected fatty acids were added, or DME-F12 with BSA. Conditioned media were collected after selected intervals and assayed for PAI-1 by ELISA (Tintelize; Biopool). Total cellular RNA was isolated conventionally with TRIzol Reagent (GIBCO BRL). Northern blotting was performed as previously described with 10 g RNA. 12 Construction of PAI-1 Promoter-Luciferase Reporter PlasmidsA 1387-bp KpnI fragment containing 1313 bp of 5Ј-flanking (Ϫ1313) and 74 bp of the untranslated first exon (ϩ74) of human PAI-1 DNA was...

show abstract

Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states.

Cited by 161 publications

References 30 publications

Hyperglycemia Stimulates Coagulation, Whereas Hyperinsulinemia Impairs Fibrinolysis in Healthy Humans

Hyperglycemia Stimulates Coagulation, Whereas Hyperinsulinemia Impairs Fibrinolysis in Healthy Humans

Relationships between Brachial Artery Flow Mediated Dilation and Carotid Artery Intima-Media Thickness in Patients with Suspected Coronary Artery Disease.

Identification and Localization of a Fatty Acid Response Region in the Human Plasminogen Activator Inhibitor-1 Gene

Contact Info

Product

Resources

About