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Biochem Biophys Res Commun. 2012 Apr 27;421(1):134-9. doi: 10.1016/j.bbrc.2012.03.138. Epub 2012 Apr 4.

Nitric oxide preserves XIAP and reduces hypoxia/reoxygenation-induced cardiomyocytes apoptosis via ERK1/2 activation.

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  • 1Department of Internal Medicine, The First Hospital of Jilin University, Changchun, China.

Abstract

The signaling pathways that control the hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis have not been fully defined. In this study, we investigated whether extracellular signal-regulated kinase1/2 (ERK1/2) plays a role in NO's anti-apoptotic effect against H/R injury. Primary cultures of adult rat ventricular myocytes (ARVMs) were exposed to 3 h of hypoxia followed by 30, 60, 90 and 120 min of reoxygenation in presence of a vehicle, NO donor (GSNO, 50 μmol/L) and inhibitors of ERK1/2 (PD98059, 10 μmol/L). GSNO protected the cardiomyocyte from reoxygenation injury, as evidenced by decreased apoptosis, and this protective effect was inhibited by co-treatment with PD98059 during reoxygenation. Consistent with this, when administered with adenoviral vector encoding dominant negative ERK (Ad-dnERK), GSNO's effect was also blocked. Western blotting revealed that GSNO increased the ERK phosphorylation during reoxygenation. Furthermore, H/R-induced activation of caspase-3 and -9 were attenuated by GSNO. Interestingly, X-linked inhibitor of apoptosis protein (XIAP) protein levels decreased in myocytes subjected to reoxygenation, and ERK phosphorylation can improve XIAP expression, which involved inhibiting caspase-3, -7 and -9 activities. Overexpression experiment with adenoviral vector containing constitutively active ERK (Ad-caERK) alone acquired protection against apoptosis triggered by H/R injury and positively regulated XIAP expression compared with control adenovirus (Ad-LacZ). Our data demonstrated that, GSNO's antiapoptotic effect against reoxygenation injury involves ERK signaling pathway. The activation of ERK increased XIAP expression and led to decreased caspase activation.

Copyright © 2012 Elsevier Inc. All rights reserved.

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