Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
JCI Insight
; 9(17)2024 Jul 25.
Article
em En
| MEDLINE
| ID: mdl-39052437
ABSTRACT
The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart; however, the rapid reintroduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the total myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and redirecting pyruvate toward oxidation can blunt hypertrophy. We hypothesized that this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. After I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨ), and Ca2+, increased pyruvate entry to the TCA cycle, increased oxygen consumption, and improved myocardial salvage and functional outcomes following I/R. Our data suggest normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Traumatismo por Reperfusão Miocárdica
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Ácido Pirúvico
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Transportadores de Ácidos Monocarboxílicos
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Miócitos Cardíacos
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Proteínas de Transporte da Membrana Mitocondrial
Limite:
Animals
Idioma:
En
Revista:
JCI Insight
Ano de publicação:
2024
Tipo de documento:
Article