Fluconazole Inhibits Cytochrome P450 1B1 and its Associated Arachidonic Acid Metabolites in the Heart and Protects against Angiotensin II‐induced Cardiac Hypertrophy
Notice bibliographique
Résumé
Cytochrome P450 1B1 (CYP1B1) has been reported to have a major role in metabolizing arachidonic acid (AA) into cardiotoxic metabolites, mid‐chain hydroxyeicosatetraenoic acid (HETEs). Of particular interest, several studies have demonstrated the role of mid‐chain HETEs in the development of cardiac hypertrophy. Recently, we have shown that fluconazole inhibits the formation of mid‐chain HETEs metabolite, however, whether fluconazole would be able to modulate CYP1B1‐mediated AA metabolism in an Ang II‐induced cellular hypertrophy model and in rats' heart has never been investigated before. Therefore, the objectives of this study were; 1) to investigate the effect of fluconazole on CYP1B1 mediated AA metabolites and to explore the potential protective effect against Ang II‐induced cellular hypertrophy, and 2) to study the effect of fluconazole on CYP1B1 and its associated AA metabolites in vivo in Sprague Dawley rats. For this purpose, both H9c2 and RL‐14 cells were treated with 10 μM Ang II in the absence and presence of 50 μM fluconazole for 24 hours. Also, Sprague Dawley rats (n=6) were injected intraperitoneally with a single dose of fluconazole (20 mg/kg) or saline and the heart tissues were harvested 24 hours post‐treatment. Thereafter, the formation of AA metabolites was measured using liquid chromatography‐electron spray ionization‐mass spectrometry (LC‐ESI‐MS). Whereas, the expression of cardiac hypertrophic markers and CYP1B1 were determined by real time‐polymerase chain reaction and Western blot analysis, respectively. Moreover, enzymatic activity and determination of CYP1B1 inhibition kinetics by fluconazole were assessed using 7‐ethoxyresorufin O‐deethylase (EROD) and recombinant human CYP1B1 assays. Our results demonstrated that fluconazole was able to attenuate Ang‐II‐induced cellular hypertrophy as evidenced by a significant inhibition of hypertrophic markers, β‐myosin heavy chain (MHC)/ α‐MHC, BNP as well as cell surface area. The protective effect of fluconazole was associated with a significant decrease in the level of CYP1B1 gene, protein, activity levels and its associated mid‐chain HETEs metabolite induced by Ang II. Furthermore, treatment of rats with fluconazole significantly decreased the expression of CYP1B1 enzyme and the formation level of cardiotoxic mid‐chain HETEs metabolites in the heart. In conclusion, our results showed that fluconazole protects against Ang II‐induced cellular hypertrophy by inhibiting CYP1B1 and its associated mid‐chain HETEs metabolites. Also, fluconazole may be repurposed as a mid‐chain HETEs formation inhibitor for the treatment of cardiac hypertrophy and heart failure. Support or Funding Information This work was supported by a grant from the Canadian Institutes of Health Research [Grant 106665] to A.O.S.E. A.H.A is the recipient of Saudi Arabian government scholarship provided by Qassim University. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
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 ».