التفاصيل البيبلوغرافية
| العنوان: |
Activin A directly impairs human cardiomyocyte contractile function indicating a potential role in heart failure development |
| المؤلفون: |
Scott MacDonnell, Jake Megna, Qin Ruan, Olivia Zhu, Gabor Halasz, Dan Jasewicz, Kristi Powers, Hock E, Maria del Pilar Molina-Portela, Ximei Jin, Dongqin Zhang, Justin Torello, Nicole T. Feric, Michael P. Graziano, Akshay Shekhar, Michael E. Dunn, David Glass, Lori Morton |
| المصدر: |
Frontiers in Cardiovascular Medicine, Vol 9 (2022) |
| بيانات النشر: |
Frontiers Media S.A., 2022. |
| سنة النشر: |
2022 |
| المجموعة: |
LCC:Diseases of the circulatory (Cardiovascular) system |
| مصطلحات موضوعية: |
hiPSC cardiomyocyte, Activin A, SERCA2a, myocardial contractility, heart failure, Diseases of the circulatory (Cardiovascular) system, RC666-701 |
| الوصف: |
Activin A has been linked to cardiac dysfunction in aging and disease, with elevated circulating levels found in patients with hypertension, atherosclerosis, and heart failure. Here, we investigated whether Activin A directly impairs cardiomyocyte (CM) contractile function and kinetics utilizing cell, tissue, and animal models. Hydrodynamic gene delivery-mediated overexpression of Activin A in wild-type mice was sufficient to impair cardiac function, and resulted in increased cardiac stress markers (N-terminal pro-atrial natriuretic peptide) and cardiac atrophy. In human-induced pluripotent stem cell-derived (hiPSC) CMs, Activin A caused increased phosphorylation of SMAD2/3 and significantly upregulated SERPINE1 and FSTL3 (markers of SMAD2/3 activation and activin signaling, respectively). Activin A signaling in hiPSC-CMs resulted in impaired contractility, prolonged relaxation kinetics, and spontaneous beating in a dose-dependent manner. To identify the cardiac cellular source of Activin A, inflammatory cytokines were applied to human cardiac fibroblasts. Interleukin -1β induced a strong upregulation of Activin A. Mechanistically, we observed that Activin A-treated hiPSC-CMs exhibited impaired diastolic calcium handling with reduced expression of calcium regulatory genes (SERCA2, RYR2, CACNB2). Importantly, when Activin A was inhibited with an anti-Activin A antibody, maladaptive calcium handling and CM contractile dysfunction were abrogated. Therefore, inflammatory cytokines may play a key role by acting on cardiac fibroblasts, causing local upregulation of Activin A that directly acts on CMs to impair contractility. These findings demonstrate that Activin A acts directly on CMs, which may contribute to the cardiac dysfunction seen in aging populations and in patients with heart failure. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2297-055X |
| Relation: |
https://www.frontiersin.org/articles/10.3389/fcvm.2022.1038114/full; https://doaj.org/toc/2297-055X |
| DOI: |
10.3389/fcvm.2022.1038114 |
| URL الوصول: |
https://doaj.org/article/754f4561a0914c0b8ad4447d62ef9577 |
| رقم الانضمام: |
edsdoj.754f4561a0914c0b8ad4447d62ef9577 |
| قاعدة البيانات: |
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