In silico study of the mechanisms of hypoxia and contractile dysfunction during ischemia and reperfusion of hiPSC cardiomyocytes.
Dis Model Mech
; 17(4)2024 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-38516812
ABSTRACT
Interconnected mechanisms of ischemia and reperfusion (IR) has increased the interest in IR in vitro experiments using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We developed a whole-cell computational model of hiPSC-CMs including the electromechanics, a metabolite-sensitive sarcoplasmic reticulum Ca2+-ATPase (SERCA) and an oxygen dynamics formulation to investigate IR mechanisms. Moreover, we simulated the effect and action mechanism of levosimendan, which recently showed promising anti-arrhythmic effects in hiPSC-CMs in hypoxia. The model was validated using hiPSC-CM and in vitro animal data. The role of SERCA in causing relaxation dysfunction in IR was anticipated to be comparable to its function in sepsis-induced heart failure. Drug simulations showed that levosimendan counteracts the relaxation dysfunction by utilizing a particular Ca2+-sensitizing mechanism involving Ca2+-bound troponin C and Ca2+ flux to the myofilament, rather than inhibiting SERCA phosphorylation. The model demonstrates extensive characterization and promise for drug development, making it suitable for evaluating IR therapy strategies based on the changing levels of cardiac metabolites, oxygen and molecular pathways.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Simulação por Computador
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Cálcio
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Miócitos Cardíacos
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ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático
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Células-Tronco Pluripotentes Induzidas
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Simendana
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Contração Miocárdica
Limite:
Animals
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Humans
Idioma:
En
Revista:
Dis Model Mech
/
Dis. model. mech. (Print)
/
Disease models & mechanisms (Online)
Assunto da revista:
MEDICINA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Finlândia