Paraoxonase 2 protects against acute myocardial ischemia-reperfusion injury by modulating mitochondrial function and oxidative stress via the PI3K/Akt/GSK-3ß RISK pathway.
J Mol Cell Cardiol
; 129: 154-164, 2019 04.
Article
en En
| MEDLINE
| ID: mdl-30802459
ABSTRACT
OBJECTIVE:
To investigate the novel role of Paraoxonase 2 (PON2) in modulating acute myocardial ischemia-reperfusion injury (IRI).APPROACH:
IRI was induced both in vivo and ex vivo in male, C57BL6/J (WT) and PON2-deficient (PON-def) mice. In addition, in vitro hypoxia-reoxygenation injury (HRI) was induced in H9c2 cells expressing empty vector (H9c2-EV) or human PON2 (H9c2-hPON2)⯱â¯LY294002 (a potent PI3K inhibitor). Infarct size, PON2 gene expression, mitochondrial calcium retention capacity (CRC), reactive oxygen species (ROS) generation, mitochondrial membrane potential, CHOP and pGSK-3ß protein levels, and cell apoptosis were evaluated.RESULTS:
PON2 gene expression is upregulated in WT mice following in vivo IRI. PON2-def mice exhibit a 2-fold larger infarct, increased CHOP levels, and reduced pGSK-3ß levels compared to WT controls. Global cardiac mitochondria isolated from PON2-def mice exhibit reduced CRC and increased ROS production. Cardiomyocytes isolated from PON2-def mice subjected to ex vivo IRI have mitochondria with reduced CRC (also seen under non-IRI conditions), and increased ROS generation and apoptosis compared to WT controls. PON2 knockdown in H9c2 cells subjected to HRI leads to an increase in mitochondrial membrane depolarization. H9c2-hPON2 cells exhibit i) improvement in mitochondrial membrane potential, pGSK-3ß levels and mitochondrial CRC, and ii) decrease in CHOP levels, mitochondrial ROS generation and cell apoptosis, when compared to H9c2-EV controls. Treatment with LY294002 resulted in a decrease of mitochondrial CRC and increase in mitochondrial ROS production and cell apoptosis in the H9c2-hPON2 group versus H9c2-EV controls.CONCLUSION:
PON2 protects against acute myocardial IRI by reducing mitochondrial dysfunction and oxidative stress in cardiomyocytes via activation of the PI3K/Akt/GSK-3ß RISK pathway.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Daño por Reperfusión Miocárdica
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Estrés Oxidativo
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Fosfatidilinositol 3-Quinasas
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Arildialquilfosfatasa
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Proteínas Proto-Oncogénicas c-akt
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Glucógeno Sintasa Quinasa 3 beta
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Mitocondrias Cardíacas
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Mol Cell Cardiol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos