1. Nitric oxide preserves XIAP and reduces hypoxia/reoxygenation-induced cardiomyocytes apoptosis via ERK1/2 activation
- Author
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Yuan, Haibo, Yan, Bo, Wang, Hejia H., Hua, Shucheng, and Hu, Aihua
- Subjects
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NITRIC oxide , *HYPOXEMIA , *HEART cells , *EXTRACELLULAR signal-regulated kinases , *X-linked inhibitor of apoptosis protein , *WESTERN immunoblotting , *LABORATORY rats , *ENZYME activation - Abstract
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 3h of hypoxia followed by 30, 60, 90 and 120min of reoxygenation in presence of a vehicle, NO donor (GSNO, 50μmol/L) and inhibitors of ERK1/2 (PD98059, 10μmol/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 &y& Elsevier]
- Published
- 2012
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