Role of ERK1/2 in the anti-apoptotic and cardioprotective effects of nitric oxide after myocardial ischemia and reperfusion |
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Authors: | D-Y Li L Tao H Liu T A Christopher B L Lopez X L Ma PhD |
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Institution: | (1) Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, PA, 19107, USA;(2) Department of Emergency Medicine, 1020 Sansom Street, Thompson Building, Room 239, Philadelphia, PA, 19107, USA;(3) Present address: Fuwai Hospital, Beijing, China |
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Abstract: | Objective: Experimental results from cultured cells suggest that there is cross-talk between nitric oxide (NO) and extracellular signal-regulated
kinase (ERK) in their anti-apoptotic effect. However, the cross-talk between these two molecules in either direction has not
been confirmed in the whole organ or whole animal level. The aim of the present study was to determine whether ERK may play
a role in the anti-apoptotic and cardioprotective effects of NO in myocardial ischemia/reperfusion (MI/R). Methods: Isolated perfused mouse hearts were subjected to 20 min of global ischemia and 120 min of reperfusion and treated with vehicle
or an NO donor (SNAP, 10 μM) during reperfusion. To determine the role of ERK1/2 in the anti-apoptotic and cardioprotective
effects of NO, hearts were pre-treated (10 min before ischemia) with U0126, a selective MEK1/2 inhibitor (1 μM). Results: Treatment with SNAP exerted significant cardioprotective effects as evidenced by reduced cardiac apoptosis (TUNEL and caspase
3 activity, p < 0.01), and improved cardiac functional recovery (p < 0.01). In addition, treatment with SNAP resulted in a 2.5-fold increase in ERK activation when compared with heart receiving
vehicle. Pre-treatment with U0126 slightly increased post-ischemic myocardial apoptosis but had no significant effect on cardiac
functional recovery in this isolated perfused heart model. However, treatment with U0126 completely blocked SNAP-induced ERK
activation and markedly, although not completely, inhibited the cardioprotection exerted by SNAP. Conclusion: These results demonstrate that nitric oxide exerts its anti-apoptotic and cardioprotective effects, at least in part, by
activation of ERK in ischemic/reperfused heart.
The first two authors contribute equally to this study. |
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Keywords: | apoptosis ERK1/2 myocardial ischemia/reperfusion nitric oxide |
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