Reduced Plasminogen Activator Inhibitor-1 Research Articles

Suppression of renin-angiotensin system (RAS) can reduce plasminogen activator inhibitor-1 (PAI-1) production in endotherial cells stimulated by chyromicron remnants (CR)

Suppression of renin-angiotensin system (RAS) can reduce plasminogen activator inhibitor-1 (PAI-1) production in endotherial cells stimulated by chyromicron remnants (CR)

Obesity, haemostasis and the fibrinolytic system.

Obese patients are at risk for the development of cardiovascular diseases, which can in part be explained by disturbances in the haemostatic and fibrinolytic systems. Indeed, obese subjects tend to have higher values of fibrinogen, factor VII, factor VIII, von Willebrand factor and plasminogen activator inhibitor compared to non-obese subjects. Abdominal obesity, in particular, has been shown to be associated with disturbances in fibrinogen, factor VIII and von Willebrand factor, while less consistent results have been found for factor VII. Recently it has been demonstrated that the adipocyte itself is able to produce plasminogen activator inhibitor-1, possibly explaining the high levels found in obesity. Different studies have investigated the association between haemostatic and fibrinolytic parameters and the insulin resistance syndrome, often present in obese subjects. Fibrinogen has been found to be related to insulin, but it has been suggested that this relationship is not independent of the accompanying inflammatory reaction. Results from studies on the relationship between insulin resistance and factor VII, factor VIII and von Willebrand factor levels are inconsistent. In contrast, plasminogen activator inhibitor-1 has been found to correlate with all components of the insulin resistance syndrome, and can be considered as a true component of this metabolic syndrome. Weight loss seems to have a beneficial effect on factor VII--probably mediated through a reduction in triglycerides. Data on factor VIII and von Willebrand factor are scarce but weight loss does not seem to have an effect. Fibrinogen does not seem to be reduced by modest weight loss and a more substantial weight loss seems necessary to lower fibrinogen levels. In contrast, both modest and substantial weight loss have been found to significantly reduce plasminogen activator inhibitor-1 levels. In conclusion, the increased cardiovascular risk observed in obesity could in part be explained by the association between insulin resistance and components of the fibrinolytic and haemostatic systems. Whether this relationship is truly causal or indirect needs to be elucidated further.

Cerivastatin, a HMG-CoA Reductase Inhibitor, Reduces Plasminogen Activator Inhibitor-1 (PAI-1) Expression in Endothelial Cells by Down-Regulation of Cellular Signaling and the Inhibition of PAI-1 Promoter Activity

Statins, which competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and reduce mevalonate synthesis, are believed to exert a plethora of pleiotropic effects. In this report, molecular mechanisms of the inhibitory effect on plasminogen activator inhibitor type 1 (PAI-1) expression produced by cerivastatin (CRV), the most active compound in this class, were studied using monocultures of human endothelial cell line (EA.hy 926). CRV similar to another statin, lovastatin (LOV), significantly inhibited PAI-1 expression and its release from endothelial cells, nonstimulated and stimulated with TNF-alpha. The inhibitory effect of CRV could be detected at the level of PAI-1 promoter in EA.hy 926 cells transfected with plasmid p800 LUC containing PAI-1 promoter fragment (+71 to -800), as well as at the level of PAI-1 mRNA. The PAI-1 promoter activity was markedly suppressed in the nonstimulated cells and almost completely inhibited in TNF-alpha-stimulated cells. In addition, CRV at low doses (IC(50) of 4 - 6 microM) significantly inhibited mitogen-activated protein kinases (MAPKs) phosphorylation. The majority of inhibitory effects occurred at significantly lower concentrations for CRV compared to LOV. The mechanism by which CRV inhibits PAI-1 expression appears to be directly associated with geranylgeranylation of some cell proteins, since the inhibitory effect on PAI-1 expression can be reversed by geranylgeranyl-pyrophosphate but not by farnesyl-pyrophosphate.

Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes.

Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentrations are characteristic for subjects with insulin resistance and could contribute to the increased cardiovascular risk in this state. In this study, we investigated the effect of troglitazone, a ligand of the nuclear receptor peroxisome proliferator activated receptor-gamma, on PAI-1 expression and secretion in human adipocytes. We used two models: in vitro differentiated subcutaneous and omental adipocytes cultured under serum-free conditions and isolated subcutaneous and omental fat cells kept in suspension culture. Plasminogen activator inhibitor-1 protein was measured by ELISA, PAI-1 mRNA by a semiquantitative RT-PCR technique. Exposure of in vitro differentiated subcutaneous adipocytes from young normal-weight females to 1 microgram/ml troglitazone for 72 h caused a reduction of both PAI-1 secretion (by 29 +/- 5%; p < 0.01) and PAI-1 mRNA expression (by 26 +/- 3%; p < 0.05). In cultures from severely obese subjects, troglitazone induced a decrease of PAI-1 antigen secretion from newly differentiated omental adipocytes by 49 +/- 8% (p < 0.01) and from subcutaneous adipocytes by 30 +/- 7% (p < 0.05). Exposure of freshly isolated subcutaneous and omental adipocytes in suspension culture to troglitazone induced a similar reduction of PAI-1 concentration in the culture medium (by 35 +/- 11%, p < 0.05, and 33 +/- 8%, p < 0.05 compared with control, respectively). This study provides evidence that troglitazone reduces PAI-1 production in human adipocytes, probably at the transcriptional level. This observation could point to a new beneficial effect of troglitazone, particularly in obese subjects, which could be associated with a reduced cardiovascular risk.

HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells.

The clinical benefit of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may derive from a qualitative, functional change in atherosclerotic lesions in addition to their lipid-lowering properties. We examined whether statins altered expression of the major determinants of fibrinolytic balance, plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator (tPA) in human vascular smooth muscle (SMC) and endothelial (EC) cells. Simvastatin reduced levels of PAI-1 antigen released from SMCs and ECs stimulated with platelet-derived growth factor or transforming growth factor-beta (IC(50) approximately 1 micromol/L). Levels of EC-derived tPA increased 2-fold over the same concentrations of simvastatin that inhibited release of PAI-1. Simvastatin's inhibitory effect was mimicked by C3 exoenzyme and prevented by geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate, suggesting the involvement of geranylgeranyl-modified intermediates. Decreased PAI-1 antigen was correlated with reduced mRNA transcription and activity of the PAI-1 promoter. By inhibiting expression of PAI-1 from SMCs and ECs while increasing expression of tPA from ECs, simvastatin may alter the local fibrinolytic balance within the vessel wall toward increased fibrinolytic capacity that, in turn, would reduce thrombotic risk after plaque rupture.

Early Thrombolysis in Acute Myocardial Infarction is Associated with Reduced Plasminogen Activator Inhibitor-1

Early Thrombolysis in Acute Myocardial Infarction is Associated with Reduced Plasminogen Activator Inhibitor-1