Li D-Y, Tao L, Liu H, Christopher T A, Lopez B L, Ma X L
Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, PA 19107, USA.
Apoptosis. 2006 Jun;11(6):923-30. doi: 10.1007/s10495-006-6305-6.
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).
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 muM) 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 muM).
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.
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.
培养细胞的实验结果表明，一氧化氮（NO）与细胞外信号调节激酶（ERK）在抗凋亡作用方面存在相互作用。然而，在整个器官或动物水平上，这两种分子在任何一个方向上的相互作用都尚未得到证实。本研究的目的是确定ERK是否在心肌缺血/再灌注（MI/R）中NO的抗凋亡和心脏保护作用中发挥作用。
将离体灌注的小鼠心脏进行20分钟的全心缺血和120分钟的再灌注，并在再灌注期间用溶媒或NO供体（SNAP，10μM）处理。为了确定ERK1/2在NO的抗凋亡和心脏保护作用中的作用，心脏在缺血前10分钟用选择性MEK1/2抑制剂U0126（1μM）进行预处理。
SNAP处理具有显著的心脏保护作用，表现为心脏凋亡减少（TUNEL和caspase 3活性，p<0.01），心脏功能恢复改善（p<0.01）。此外，与接受溶媒的心脏相比，SNAP处理导致ERK激活增加2.5倍。在这个离体灌注心脏模型中，U0126预处理略微增加了缺血后心肌凋亡，但对心脏功能恢复没有显著影响。然而，U0126处理完全阻断了SNAP诱导的ERK激活，并显著（尽管不是完全）抑制了SNAP发挥的心脏保护作用。
这些结果表明，一氧化氮至少部分地通过激活缺血/再灌注心脏中的ERK发挥其抗凋亡和心脏保护作用。
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