• Dawoud Sulaiman, Jingyuan Li, Asokan Devarajan, Christine Marie Cunningham, Min Li, Gregory A Fishbein, Alan M Fogelman, Mansoureh Eghbali, and Srinivasa T Reddy.
• Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, United States of America; Molecular Toxicology Interdepartmental Degree Program, University of California, Los Angeles, United States of America.
• J. Mol. Cell. Cardiol. 2019 Apr 1; 129: 154-164.

ObjectiveTo investigate the novel role of Paraoxonase 2 (PON2) in modulating acute myocardial ischemia-reperfusion injury (IRI).ApproachIRI 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) ± 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-3β protein levels, and cell apoptosis were evaluated.ResultsPON2 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-3β 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-3β 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.ConclusionPON2 protects against acute myocardial IRI by reducing mitochondrial dysfunction and oxidative stress in cardiomyocytes via activation of the PI3K/Akt/GSK-3β RISK pathway.Copyright © 2019. Published by Elsevier Ltd.

42 keywords...

hide…