Regulation of Na+-K+-ATPase leads to disturbances of isoproterenol-induced cardiac dysfunction via interference of Ca2+-dependent cardiac metabolism.
Clin Sci (Lond)
; 138(1): 23-42, 2024 01 10.
Article
em En
| MEDLINE
| ID: mdl-38060817
ABSTRACT
Reductions in Na+-K+-ATPase (NKA) activity and expression are often observed in the progress of various reason-induced heart failure (HF). However, NKA α1 mutation or knockdown cannot cause spontaneous heart disease. Whether the abnormal NKA α1 directly contributes to HF pathogenesis remains unknown. Here, we challenge NKA α1+/- mice with isoproterenol to evaluate the role of NKA α1 haploinsufficiency in isoproterenol (ISO)-induced cardiac dysfunction. Genetic knockdown of NKA α1 accelerated ISO-induced cardiac cell hypertrophy, heart fibrosis, and dysfunction. Further studies revealed decreased Krebs cycle, fatty acid oxidation, and mitochondrial OXPHOS in the hearts of NKA α1+/- mice challenged with ISO. In ISO-treated conditions, inhibition of NKA elevated cytosolic Na+, further reduced mitochondrial Ca2+ via mNCE, and then finally down-regulated cardiac cell energy metabolism. In addition, a supplement of DRm217 alleviated ISO-induced heart dysfunction, mitigated cardiac remodeling, and improved cytosolic Na+ and Ca2+ elevation and mitochondrial Ca2+ depression in the NKA α1+/- mouse model. The findings suggest that targeting NKA and mitochondria Ca2+ could be a promising strategy in the treatment of heart disease.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Miócitos Cardíacos
/
Insuficiência Cardíaca
Limite:
Animals
Idioma:
En
Revista:
Clin Sci (Lond)
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China