Concentration-dependent wrestling between detrimental and protective effects of H2O2 during myocardial ischemia/reperfusion.
Concentration-dependent wrestling between detrimental and protective effects of H2O2 during myocardial ischemia/reperfusion.
复制标题
心肌缺血/再灌注期间 H2O2 的有害作用和保护作用之间的浓度依赖性角力
DOI：
10.1038/cddis.2014.267
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发表时间：
2014-06-19
影响因子：
9
通讯作者：
Yang HT
中科院分区：
文献类型：
--
作者：
Wang ZH;Liu JL;Wu L;Yu Z;Yang HT
活性氧（ROS）和内质网（ER）应激与心肌缺血/再灌注（I/R）损伤和心脏保护有矛盾的关系。然而，对于在I/R过程中ROS的双重作用及其与内质网应激的关系的精确解释仍然是难以捉摸的。本研究采用离体大鼠心肌I/R模型，研究过氧化氢（H2O2）预处理（PC）和后适应（PoC）对内质网应激和促存活再灌注损伤挽救激酶（RISK）激活的浓度依赖性影响。H2O2对PC和PoC的影响表现为三个阶段。低浓度（1 μM） H2O2可加重I/ r诱导的左心室（LV）收缩功能障碍和内质膜应激，表现为蛋白激酶样内质膜激酶磷酸化增强，葡萄糖调节蛋白78、x- box结合蛋白1剪接变体、TNF受体相关因子2、活化转录因子6切割50 kDa片段和caspase-12切割表达增强。但I/ r诱导的风险激活包括蛋白激酶B （PKB/Akt）和蛋白激酶C / (PKC /)保持不变。同样，4-苯基丁酸抑制内质酸应激可改善1 μM H2O2 PC组和PoC组的缺血后LV性能，但内质酸应激诱导剂tunicamycin对其无影响。在中等浓度（10-100 μM）下，H2O2显著改善了缺血后左室性能，增强了RISK激活，但没有进一步改变内质电应激。Akt或PKC α抑制剂wortmannin或α V1-2均可消除心肌保护作用，但未消除内质网应激。高浓度（1 mM） H2O2可显著加重再灌注损伤和氧化应激，但不能进一步增强风险激活。此外，1 μM或20 μM的H2O2 PC没有改变缺血PC在缺血后收缩性能和蛋白质氧化方面的心脏保护作用。我们的数据表明，H2O2的不同影响源于其有害应激和保护信号之间的浓度依赖角力。
Reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress are paradoxically implicated in myocardial ischemia/reperfusion (I/R) injury and cardioprotection. However, the precise interpretation for the dual roles of ROS and its relationship with the ER stress during I/R remain elusive. Here we investigated the concentration-dependent effects of hydrogen peroxide (H2O2) preconditioning (PC) and postconditioning (PoC) on the ER stress and prosurvival reperfusion injury salvage kinase (RISK) activation using an ex vivo rat myocardial I/R model. The effects of H2O2 PC and PoC showed three phases. At a low level (1 μM), H2O2 exacerbated I/R-induced left ventricular (LV) contractile dysfunction and ER stress, as indicated by enhanced phosphorylation of protein kinase-like ER kinase and expressions of glucose-regulated protein 78, X-box-binding protein 1 splicing variant, TNF receptor-associated factor 2, activating transcription factor-6 cleaved 50 kDa fragment, and caspase-12 cleavage, but the I/R-induced RISK activation including protein kinase B (PKB/Akt) and protein kinase Cɛ (PKCɛ) remained unchanged. Consistently, the postischemic LV performance in 1 μM H2O2 PC and PoC groups was improved by inhibiting ER stress with 4-phenyl butyric acid but not affected by the ER stress inducer, tunicamycin. At a moderate level (10–100 μM), H2O2 significantly improved postischemic LV performance and enhanced RISK activation, but it did no further alter the ER stress. The cardioprotection but not ER stress was abrogated with Akt or PKCɛ inhibitor wortmannin or ɛV1–2. At a high level (1 mM), H2O2 markedly aggravated the reperfusion injury and the oxidative stress but did not further enhance the RISK activation. In addition, 1 or 20 μM of H2O2 PC did not alter cardioprotective effects of ischemic PC in postischemic contractile performance and protein oxidation. Our data suggest that the differential effects of H2O2 are derived from a concentration-dependent wrestling between its detrimental stress and protective signaling.