title: Physiological testosterone stimulates tissue plasminogen activator and tissue factor pathway inhibitor and inhibits plasminogen activator inhibitor type 1 release in endothelial cells.
abstract: 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 cm(2) flasks or plated onto 96-well plates with a density of about 1 x 10(5) cells/mL as recommended. The cells were incubated in the presence or absence of testosterone (3, 30, 3 x 10(3), 3 x 10(4) 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 micromol/L) or aromatase inhibitor (aminoglutethimide 50 micromol/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 x 10(4) nmol/L). On the other hand, PAI-1 antigen levels decreased significantly at the testosterone concentrations ranging from 3 to 3 x 10(4) 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.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong 515041, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.forename: Jijin
authors.initials: J
authors.lastname: Lin
authors.forename: Lu
authors.initials: L
authors.lastname: Fu
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Mei
authors.forename: Geng
authors.initials: G
authors.lastname: Peng
authors.forename: Xuerui
authors.initials: X
authors.lastname: Tan
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yu-Guang
authors.initials: YG
authors.lastname: Li
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D008074:Lipoproteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D010960:Plasminogen Activators / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D008074:Lipoproteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; C051928:lipoprotein-associated coagulation inhibitor; D013739:Testosterone; D005485:Flutamide; D010960:Plasminogen Activators