Regulation of the Gene Encoding Human Thrombin-Activable Fibrinolysis Inhibitor by Female Sex Steroids
Notice bibliographique
Résumé
Abstract Thrombin-activable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme that, once activated by thrombin, the thrombin-thrombomodulin complex, or plasmin, attenuates fibrinolysis. Aberrant regulation of the TAFI pathway alters the balance between coagulation and fibrinolysis and may underlie severe haemostatic disorders such as thrombosis and hemophilia. Indeed, high plasma TAFI levels have been associated with several cardiovascular diseases. It is important to note that there is a large inter-individual variability in plasma TAFI levels within the population, and this variation is primarily due to non-genetic factors. Therefore, variation in TAFI gene expression is a risk factor for thrombotic disorders and may be an important means by which TAFI responds to environmental and physiological stimuli. Novel associations between plasma TAFI levels and sex hormones have triggered interest in determining the role of TAFI as a mediator of the cardioprotective effects of estrogens and progestagens, or as a mediator of the increased thrombotic risk that accompanies use of oral contraceptives or hormone replacement therapy. Plasma TAFI concentrations rise with age in women but not in men, and are elevated in post-menopausal women compared to pre-menopausal women. In addition, plasma TAFI levels have been shown to be decreased by selective estrogen receptor modulators such as HMR 3339 and raloxifene, estradiol plus trimegestone, transdermal estradiol, and oral estradiol plus gestodene. On the other hand, some studies have reported minimal to no change in plasma TAFI levels occurring with the use of oral contraceptive, Raloxifene, or Tamoxifen. Paradoxically, it has been shown that both plasma TAFI levels and clot lysis time rise during pregnancy and then promptly return to basal levels after delivery. These studies illustrate the controversies surrounding the role of sex steroids in modulating plasma TAFI levels. In the present study, we have attempted to directly measure the effect of sex steroids on hepatic TAFI gene expression, and to uncover the molecular mechanisms underlying these regulatory events. HepG2 (human hepatocellular carcinoma) cells were cultured in the presence or absence of progesterone and b-estradiol and TAFI mRNA abundance was measured using real-time RT-PCR. We found that both of these hormones significantly decrease endogenous TAFI mRNA abundance in a dose-dependant manner. To assess the ability of these hormones to influence transcription of the gene encoding TAFI, we treated HepG2 cells that had been transiently transfected with luciferase reporter plasmids containing the 5′-flanking region of the TAFI gene. Interestingly, the change in promoter activity closely paralleled changes in mRNA abundance, suggesting that the effect of the hormones is mediated at the level of transcription. Furthermore, changes in TAFI mRNA abundance following treatments with estrogen were not associated with a decrease in TAFI mRNA stability when compared to the untreated control. TAFI protein levels were also decreased in a dose-dependent manner as assessed by western blot analysis. Inspection of the sequence of the TAFI 5′-flanking region does not show any consensus estrogen responsive elements, although we cannot exclude a role for more complex transcriptional system such as an estrogen response unit. The effect of estrogen could also be performed indirectly through the modulation of other transcription factors such SP-1 or members of the basal transcriptional machinery. We also investigated whether progesterone decreases TAFI gene expression via the binding of the progesterone receptor to the established glucocorticoid responsive element (GRE) within the TAFI promoter. Our results showed that progesterone generates the same decrease in promoter activity even when the GRE site was mutated, indicating that progesterone may act through a different site. In conclusion, our studies are beginning to reveal the molecular basis for the apparent relationship between female sex steroids and plasma concentrations of TAFI: specifically, a direct downregulatory effect on transcription of the gene encoding TAFI.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».