Physiological testosterone stimulates tissue plasminogen activator and tissue factor pathway inhibitor and inhibits plasminogen activator inhibitor type 1 release in endothelial cellsThis paper is one of a selection of papers in this Special Issue, entitled International Symposium on Recent Advances in Molecular, Clinical, and Social Medicine, and has undergone the Journal's usual peer-review process.

2007 ◽  
Vol 85 (2) ◽  
pp. 246-251 ◽  
Author(s):  
Hong Jin ◽  
Jijin Lin ◽  
Lu Fu ◽  
Yi-Fang Mei ◽  
Geng Peng ◽  
...  

There is a striking gender difference in atherosclerotic vascular disease. For decades, testosterone was considered detrimental to the cardiovascular system. Recent studies, however, have presented some alternative results. The aim of this study was to evaluate the effect of testosterone, using physiological and supraphysiological concentrations, on antigen and mRNA levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), and tissue factor pathway inhibitor (TFPI) released by human umbilical vein endothelial cells and to investigate the cellular mechanism. Cells within 2–3 passages were cultured in 25 cm2 flasks or plated onto 96-well plates with a density of about 1 × 105 cells/mL as recommended. The cells were incubated in the presence or absence of testosterone (3, 30, 3 × 103, 3 × 104 nmol/L) for 48 h. Levels of tPA, PAI-1, and TFPI antigen were assayed with ELISA kits. Reverse transcriptase PCR was carried out to detect tPA, PAI-1, and TFPI mRNA levels. Cells were incubated in androgen-receptor antagonist (flutamide 10 µmol/L) or aromatase inhibitor (aminoglutethimide 50 µmol/L) for 3 h, and then the experiments were repeated. Testosterone at a physiologic concentration (30 nmol/L) increased the antigen levels of tPA and TFPI significantly (P < 0.05). However, tPA and TFPI levels were markedly reduced (P < 0.05) at a larger dose (3 × 104 nmol/L). On the other hand, PAI-1 antigen levels decreased significantly at the testosterone concentrations ranging from 3 to 3 × 104 nmol/L (P < 0.05). The change in the levels of tPA and TFPI were reflected in the corresponding change in mRNA levels. Flutamide attenuated the effect of testosterone at physiological concentration (30 nmol/L). The results demonstrated that testosterone at physiological concentrations may have a beneficial influence on the haemostatic system through enhancement of anticoagulant activity, resulting from stimulation of TFPI and tPA expression and inhibition of PAI-1 secretion by the endothelium.

2001 ◽  
Vol 12 (6) ◽  
pp. 1255-1263 ◽  
Author(s):  
ALFONS SEGARRA ◽  
PILAR CHACÓN ◽  
CRISTINA MARTINEZ-EYARRE ◽  
XAVIER ARGELAGUER ◽  
JOSEFA VILA ◽  
...  

Abstract. This study investigated the relationship between the circulating levels of the endothelial cell glycoproteins plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (TPA), and thrombomodulin (TM) and the major vascular risk factors described in dialysis patients. In addition, the role of these endothelial cell products as independent predictors of coronary artery disease (CAD) was analyzed. Levels of TM, TPA antigen (Ag), TPA activity, PAI-1 Ag, PAI-1 activity, TPA/PAI complexes, thrombin-antithrombin complexes, fibrinopeptide A, C-reactive protein (CRP), interleukin-1β and tumor necrosis factor-α, lipids, apoproteins A1 and B, and albumin were measured in a group of 200 nondiabetic dialysis patients and 100 healthy matched volunteers. When compared with healthy controls, dialysis patients showed increased levels of CRP, TM, TPA, and PAI-1 and evidence of increased thrombin-dependent fibrin formation. Increased levels of active PAI-1 were associated to a great extent with major classic vascular risk factors and to a lesser extent with CRP and serum triglycerides. Forty-six patients (23%) had evidence of CAD. Variables associated with CAD in the univariate analysis included age, time on dialysis, male gender, number of packs of cigarettes per year, high BP, fibrinogen, apolipoprotein B, albumin, PAI-1 activity, CRP, thrombin-antithrombin complexes, and fibrinopeptide A. Logistic regression analysis found age, high-density lipoprotein cholesterol, gender, high BP, CRP, time on dialysis, and PAI-1 activity to be independent predictors of CAD. This model classified correctly 85% of patients as having CAD and showed adequate goodness of fit for all risk categories. Our data support a pathogenic link among activated inflammatory response, endothelial injury, and CAD in hemodialysis patients and suggest that assessment of circulating PAI-1 levels could be an additional tool to identify dialysis patients who are at risk for developing atheromatous cardiovascular disease.


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