Wnt/β-catenin signaling regulates cardiac Cx43 in a metabolic substrate-dependent manner
Notice bibliographique
Résumé
Both Na v 1.5 and Cx43 are critical for the fast electrical impulse conduction in the myocardium and their reductions create the arrhythmogenic substrate. The Wnt/β-catenin signaling is activated in arrhythmogenic myocardium, and although this signaling is known to downregulate cardiac Na v 1.5, its regulation of Cx43 is unclear as conflicting results have been reported. The present study investigated how Wnt/β-catenin signaling regulates Cx43 in rat and human cardiomyocytes and if it is dependent on the sex of the cells or the metabolic substrates. Male and female neonatal rat ventricular myocytes (NRVMs) were treated with CHIR-99021 (CHIR) or Wnt3a protein, two different activators of the Wnt/β-catenin signaling, either in a medium rich in glucose (a preferred metabolic substrate in heart failure) or in a medium rich in lipid (~150 μM fatty acid, a preferred substrate in healthy hearts). Both healthy and Brugada Syndrome human iPSC-derived cardiomyocytes (iPSC-CMs) were used to confirm observations in NRVMs. When maintained in a glucose-rich medium, Gja1 mRNA (encoding Cx43) was reduced by a low concentration of CHIR (1 μM) in female NRVMs but only at a high concentration of CHIR (10 μM) in male NRVMs. However, reductions in Cx43 protein were observed at 1 μM CHIR in both male and female NRVMs, suggesting the involvement of both transcriptional and post-transcriptional mechanisms. When maintained in a lipid-rich medium, neither Gja1 mRNA nor Cx43 protein was altered by CHIR at 1 or 3 μM. In contrast, CHIR-induced reductions in Scn5a mRNA and Na v 1.5 protein were observed in both glucose-rich and lipid-rich media, with no significant sex-specific differences detected. Consistent with studies using CHIR, which is a Wnt receptor-independent activator, Wnt3a protein also reduced both Gja1 mRNA and Cx43 protein in NRVMs in the glucose-rich medium but not in the lipid-rich medium. In human iPSC-CMs from two healthy volunteers and one Brugada Syndrome patient, Wnt/β-catenin signaling activation reduced both GJA1 mRNA and Cx43 protein in a standard, glucose-containing medium. These data demonstrate that metabolic substrates regulate the effects of Wnt/β-catenin signaling in cardiomyocytes, with reductions in Cx43 mRNA and protein only observed when glucose is the primary metabolic substrate, which occurs in arrhythmogenic conditions such as cardiac hypertrophy and heart failure. • Metabolic substrates regulate the effects of Wnt/β-catenin signaling in cardiomyocytes. • Wnt/β-catenin signaling reduces both cardiac Cx43 and Na v 1.5 when glucose is the primary metabolic substrate. • Wnt/β-catenin signaling reduces cardiac Na v 1.5, but not Cx43, when fatty acids are the primary metabolic substrate. • Wnt/β-catenin signaling may contribute to the arrhythmogenesis in heart failure when glucose is the preferred substrate.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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) | 0,000 | 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 tête enseignante, 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 ».