The Role of GSK3β in SERCA Dysfunction and the Development of Arrhythmogenic Cardiomyopathy
Notice bibliographique
Résumé
The sarco(endo)plasmic reticulum Ca 2+ ‐ATPase (SERCA) pump catalyzes the active transport of Ca 2+ into the sarcoplasmic reticulum and is responsible for over 70% of Ca 2+ turnover after muscle contraction. Phospholamban (PLN) is a well‐known SERCA regulator, and impaired SERCA function due to reductions in SERCA and/or enhanced inhibitory PLN action has been linked to the development of various cardiomyopathies. Arrhythmogenic cardiomyopathy (ACM) is an inherited, non‐ischemic heart disease presenting with ventricular arrhythmias, hypo/dyskinesia, and fibrotic remodeling. Over 60% of ACM cases are caused by pathogenic variants in genes encoding the cardiac desmosome, where Desmoglein‐2 ( DSG2 ) is the second most prevalent desmosomal gene variant in the ACM patient population. Using Dsg2 mutant ( Dsg2 mut/mut ) mice, previous studies showed that the enzyme glycogen synthase kinase‐3β (GSK3β), plays a major role in ACM pathogenesis. Inhibiting GSK3β in these mice improved cardiac contractility and ACM pathological phenotypes. We have shown that GSK3β inhibition in cardiomyocytes can also improve SERCA function in wild‐type (WT) mice; however, the role of GSK3β activity on SERCA function in Dsg2 mut/mut mice is currently unknown. Here, we sought to examine the effects of GSK3β inhibition on SERCA function using a GSK3β‐specific inhibitor, SB216763 (SB2), in Dsg2 mut/mut mice. At 3 weeks of age, both WT and Dsg2 mut/mut mice were treated with SB2 (2.5 mg/kg/day) or equivalent volume/kg/day of vehicle (DMSO) for 13 weeks via intraperitoneal injection. After treatment, mice were sacrificed and hearts were collected and homogenized. Our results show that cardiomyocytes obtained from vehicle treated Dsg2 mut/mut mice had significantly lower SERCA2a expression (‐52%, p <0.01) compared to vehicle treated WT mice, leading to reduced SERCA2a:PLN (‐65%, p =0.04). Maximal SERCA activity was also significantly lower in vehicle treated Dsg2 mut/mut mice (‐65%, p =0.001). However, in myocardium from SB2 treated Dsg2 mut/mut mice, maximal SERCA activity, SERCA2a expression, and SERCA2a:PLN ratio were all restored to near WT levels. We also examined the effects of heterozygous and homozygous GSK3β S9A mutation in the Dsg2 mut/mut mice, which prevents phosphorylation and maintains GSK3β in its constitutively active form. When comparing WT with Dsg2 mut/mut heterozygous and homozygous GSK3β S9A mutants, we saw a significant but non‐progressive decrease in maximal SERCA activity (‐60%, p =0.02 and ‐58%, p =0.03 respectively). In conclusion, these results show that SERCA function is negatively impacted in Dsg2 mut/mut cardiomyocytes. Conversely, GSK3β inhibition with SB2 treatment improved SERCA content and activity to healthy WT levels. These results further illuminate the role of GSK3β in ACM pathogenesis and support the use of GSK3β inhibitors in its treatment, as our new promising results indicate this therapeutic strategy can also improve Ca 2+ handling.
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 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 | 0,003 | 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) | 0,000 | 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 ».