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

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• 作者：Haibo Yuan^a ; ^d ; Bo Yan^b ; Hejia H. Wang^c ; Shucheng Hua^a ; ^{shuchenghua@eyou.com} ; Aihua Hu^d ; ^{hua@email.chop.edu}
• 关键词：ERK1/2 ; XIAP ; Apoptosis ; Cardiomyocyte ; Reoxygenation
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：27 April, 2012
• 卷：421
• 期：1
• 页码：134-139
• 文件大小：744 K

摘要

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鈥檚 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 渭mol/L) and inhibitors of ERK1/2 (PD98059, 10 渭mol/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鈥檚 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鈥檚 antiapoptotic effect against reoxygenation injury involves ERK signaling pathway. The activation of ERK increased XIAP expression and led to decreased caspase activation.