H2O2-induced Ca2+ overload in NRVM involves ERK1/2 MAP kinases:: role for an NHE-1-dependent pathway
H2O2-induced Ca2+ overload in NRVM involves ERK1/2 MAP kinases:: role for an NHE-1-dependent pathway
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DOI：
10.1152/ajpheart.00198.2002
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发表时间：
2002-08-01
影响因子：
4.8
通讯作者：
Lucchesi, PA
中科院分区：
文献类型：
--
作者：
Rothstein, EC;Byron, KL;Lucchesi, PA
活性氧（ROS）的产生和细胞内Ca2+超载是缺血再灌注（I/R）诱导的心肌损伤的关键机制。I/R损伤与Ca2+超载之间的关系尚未得到充分表征。在I/R损伤期间观察到的Na+/H+交换器（NHE-1）活性的增加是将ROS产生增加与Ca2+过载联系起来的一个有吸引力的候选。我们已经证明，低剂量的H2O2以细胞外信号调节激酶（ERK）依赖的方式增加NHE-1活性。在这项研究中，我们研究了低剂量H2O2对fura 2负载的细胞内Ca2+的影响，自发收缩新生大鼠心室肌细胞。H2O2诱导舒张期细胞内Ca2+浓度随时间和浓度的增加，通过5 muM U-0126抑制ERK1/2激活（88%）或5 muM HOE-642抑制NHE-1（50%）来阻断。NHE活性的增加与NHE-1羧基尾部的磷酸化有关，该磷酸化被U-0126阻断。这些结果表明，H2O2诱导的Ca2+过载部分是由ERK1/2 MAP激酶途径介导的NHE-1磷酸化后的NHE-1活化介导的。
Generation of reactive oxygen species (ROS) and intracellular Ca2+ overload are key mechanisms involved in ischemia-reperfusion (I/R)-induced myocardial injury. The relationship between I/R injury and Ca2+ overload has not been fully characterized. The increase in Na+/H+ exchanger (NHE-1) activity observed during I/R injury is an attractive candidate to link increased ROS production with Ca2+ overload. We have shown that low doses of H2O2 increase NHE-1 activity in an extracellular signal-regulated kinase (ERK)-dependent manner. In this study, we examined the effect of low doses of H2O2 on intracellular Ca2+ in fura 2-loaded, spontaneously contracting neonatal rat ventricular myocytes. H2O2 induced a time- and concentration-dependent increase in diastolic intracellular Ca2+ concentration that was blocked by inhibition of ERK1/2 activation with 5 muM U-0126 (88%) or inhibition of NHE-1 with 5 muM HOE-642 (50%). Increased NHE activity was associated with phosphorylation of the NHE-1 carboxyl tail that was blocked by U-0126. These results suggest that H2O2 induced Ca2+ overload is partially mediated by NHE-1 activation secondary to phosphorylation of NHE-1 by the ERK1/2 MAP kinase pathway.