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Heart failure-induced cognitive dysfunction is mediated by intracellular Ca(2+) leak through ryanodine receptor type 2

Cognitive dysfunction (CD) in heart failure (HF) adversely affects treatment compliance and quality of life. Although ryanodine receptor type 2 (RyR2) has been linked to cardiac muscle dysfunction, its role in CD in HF remains unclear. Here, we show in hippocampal neurons from individuals and mice w...

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Detalles Bibliográficos
Autores principales: Dridi, Haikel, Liu, Yang, Reiken, Steven, Liu, Xiaoping, Argyrousi, Elentina K., Yuan, Qi, Miotto, Marco C., Sittenfeld, Leah, Meddar, Andrei, Soni, Rajesh Kumar, Arancio, Ottavio, Lacampagne, Alain, Marks, Andrew R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400432/
https://www.ncbi.nlm.nih.gov/pubmed/37429912
http://dx.doi.org/10.1038/s41593-023-01377-6
Descripción
Sumario:Cognitive dysfunction (CD) in heart failure (HF) adversely affects treatment compliance and quality of life. Although ryanodine receptor type 2 (RyR2) has been linked to cardiac muscle dysfunction, its role in CD in HF remains unclear. Here, we show in hippocampal neurons from individuals and mice with HF that the RyR2/intracellular Ca(2+) release channels were subjected to post-translational modification (PTM) and were leaky. RyR2 PTM included protein kinase A phosphorylation, oxidation, nitrosylation and depletion of the stabilizing subunit calstabin2. RyR2 PTM was caused by hyper-adrenergic signaling and activation of the transforming growth factor-beta pathway. HF mice treated with a RyR2 stabilizer drug (S107), beta blocker (propranolol) or transforming growth factor-beta inhibitor (SD-208), or genetically engineered mice resistant to RyR2 Ca(2+) leak (RyR2-p.Ser2808Ala), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness driven by intracellular Ca(2+) leak that includes cardiogenic dementia.