Distinct remodeling pattern between pediatric and adult heart failure: a focus on Ca2+ signaling pathway at proteomic level
Notice bibliographique
Résumé
Abstract Background Dilated cardiomyopathy (DCM) is among the most common causes leading to end-stage heart failure with reduced ejection fraction (HF-rEF) in adult and pediatric patients. Despite similar phenotypes characterized as systolic dysfunction and eccentric ventricular dilation, pediatric DCM are biologically distinct entities with age- and development-specific features in the heart. Though underlying mechanisms may vary between the two populations, it's largely unexplored with few studies conducted to date. Purpose HF-rEF typically results from impaired myocardial contractility, triggered by defective cellular Ca2+ handling and cytoskeletal remodeling. Hence, we aim to integrate clinical profile and experimental data from human explanted hearts: 1) to unravel the age-dependent disparate Ca2+ signaling pathways; and 2) to identify pediatric-specific HF signatures or potential cures for precision managements. Methods Non-ischemic failing hearts (n=6 adult and n=6 pediatric) were procured immediately after excision via Human Explanted Heart Program. Age-matched adult non-failing control hearts (NFC, n=6) were obtained from deceased donors without cardiovascular history, while pediatric NFC (n=6) were collected from children with congenital heart defects but no primary myocardial dysfunction constituting relatively reasonable controls. Myocardial metabolic and oxidative profile were evaluated spectrophotometrically, and tissue remodeling was assessed immunohistochemically. Global proteomics and phosphoproteomics were performed on a Q-Exactive mass spectrometer, followed by network biology pathway analyses. Expression of screened proteins and kinases was validated by gel electrophoresis. Apoptosis and cellular growth signaling pathways were also incorporated into analysis. Results Both HF groups had remarkably lower LVEF (26.6±10.7% in pediatric vs. 26.5±9.1% in adult DCM) while compared to the NFC (both ≥60%) respectively. Histologically, adult-DCM demonstrated significantly worse fibrosis than pediatric-DCM (p<0.01). It was consistent with excessive reactive oxygen species (ROS) production and perturbed anti-ROS defense noted in adult-DCM, indicative of possible reverse remodeling in the pediatric failing hearts with shorter course of illness till transplant. Mechanistically, NCX1 was elevated with SERCA2 decreased in adult-DCM versus adult-NFC (p<0.05), while both pediatric groups exhibited comparable levels. Reduced p-/t-phospholamban and p-/t-CaMK in adult-DCM, unlike in pediatric-DCM, also illustrated altered phosphorylation patterns. Moreover, GSK-3β and AMPK pathways were inhibited while AKT-473 was activated in adult-DCM. Conclusions Pediatric DCM exhibited less adverse remodeling partially mediated by divergent Ca2+ handling and downstream signaling pathways, illustrating the fundamental differences between adult and pediatric DCM. Our findings may provide a scientific basis for the development of specific therapies for pediatric DCM. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Canadian Institutes for Health Research (CIHR); Heart & Stroke Foundation (HSF)
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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 | 0,001 |
| 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 ».