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c-Src Is Responsible for Mitochondria-Mediated Arrhythmic Risk in Ischemic Cardiomyopathy.
Xie, An; Kang, Gyeoung-Jin; Kim, Eun Ji; Liu, Hong; Feng, Feng; Dudley, Samuel C.
Afiliación
  • Xie A; Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis.
  • Kang GJ; Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis.
  • Kim EJ; Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis.
  • Liu H; Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis.
  • Feng F; Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis.
  • Dudley SC; Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis.
Circ Arrhythm Electrophysiol ; : e013054, 2024 Aug 30.
Article en En | MEDLINE | ID: mdl-39212055
ABSTRACT

BACKGROUND:

Increased mitochondrial Ca2+ uptake has been implicated in the QT prolongation and lethal arrhythmias associated with nonischemic cardiomyopathy. We attempted to define the role of mitochondria in ischemic arrhythmic risk and to identify upstream regulators.

METHODS:

Myocardial infarction (MI) was induced in wild-type FVB/NJ mice by ligation of the left anterior descending coronary artery. Western blot, immunoprecipitation, ECG telemetry, and patch-clamp techniques were used.

RESULTS:

After MI, c-Src (proto-oncogene tyrosine-protein kinase Src) and its active form (p-Src Y416) were increased. The activation of c-Src was associated with increased diastolic Ca2+ sparks, action potential duration prolongation, and arrhythmia in MI mice. c-Src upregulation and arrhythmia could be reversed by treatment of mice with the Src inhibitor PP1 but not with the inactive analogue PP3. Tyrosine phosphorylated mitochondrial Ca2+ uniporter (MCU) was upregulated in the heart tissues of MI mice and patients with ischemic cardiomyopathy. In a heterologous expression system, c-Src could bind MCU and phosphorylate MCU tyrosines. Overexpression of wild-type c-Src significantly increased the mitochondrial Ca2+ transient while overexpression of dominant-negative c-Src significantly decreased the mitochondrial Ca2+ transient. c-Src inhibition by PP1, MCU inhibition by Ru360, or MCU knockdown could reduce the action potential duration, Ca2+ sparks, and arrhythmia after MI. The human heart tissue showed that patients with ischemic cardiomyopathy had significantly increased c-Src active form associated with increased MCU tyrosine phosphorylation and ventricular arrhythmia.

CONCLUSIONS:

MI leads to increased c-Src active form that results in MCU tyrosine phosphorylation, increased mitochondrial Ca2+ uptake, QT prolongation, and arrhythmia, suggesting c-Src or MCU may represent novel antiarrhythmic targets.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Circ Arrhythm Electrophysiol Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Circ Arrhythm Electrophysiol Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos