Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through ryanodine receptor type 2.
Nat Neurosci
; 26(8): 1365-1378, 2023 08.
Article
em En
| MEDLINE
| ID: mdl-37429912
ABSTRACT
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 Ca2+ 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 Ca2+ leak (RyR2-p.Ser2808Ala), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness driven by intracellular Ca2+ leak that includes cardiogenic dementia.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Canal de Liberação de Cálcio do Receptor de Rianodina
/
Disfunção Cognitiva
/
Insuficiência Cardíaca
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Nat Neurosci
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos