δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) mediate intermittent hypoxia induced protection of canine myocardium
δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) mediate intermittent hypoxia induced protection of canine myocardium
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DOI：
10.1007/s00395-016-0538-5
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发表时间：
2016-03-01
影响因子：
9.5
通讯作者：
Mallet, Robert T.
中科院分区：
文献类型：
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作者：
Estrada, Juan A.;Williams, Arthur G., Jr.;Mallet, Robert T.
间歇性、常压缺氧对缺血性心肌梗死和致死性室性心律失常具有强大的心脏保护作用。delta-阿片受体（DOR）信号和活性氧（ROS）与心脏保护现象有关，但它们在间歇性缺氧中的作用尚不清楚。本研究探讨DOR和ROS在介导间歇性缺氧诱导的心脏保护中的作用。杂种狗完成了一个为期20天的项目，包括每天5-8次，5-10分钟的中度、常压缺氧周期（FIO2 0.095-0.10），中间4分钟的室内空气暴露。各组狗在每次缺氧前给予DOR拮抗剂纳曲多（200 μ g/kg, sc）或抗氧化剂n -乙酰半胱氨酸（250 mg/kg, po）。末次疗程24 h后，阻断左冠状动脉前降支60 min，再灌注5 h。心电图检测到的心律失常按Lambeth II惯例评分。左心室切片，用2,3,5-三苯四唑-氯化染色，梗死面积表示为危险面积的百分比（IS/AAR）。与非缺氧对照组相比，间歇性缺氧使IS/AAR从41 +/- 5% （n = 12）急剧下降至1.8 +/- 0.9% (n = 9; P < 0.001)，心律失常评分从4.1 +/- 0.3降至0.7 +/- 0.2 （P < 0.001）。纳曲多（n = 6）在IS/AAR值为35 +/- 5%，心律失常评分为3.7 +/- 0.7时（与未治疗的间歇缺氧相比P < 0.001）取消了心脏保护作用。n -乙酰半胱氨酸（n = 6）的干扰程度相似，IS/AAR为42 +/- 3%，心律失常评分为4.7 +/- 0.3（与未治疗的间歇性缺氧相比，P < 0.001）。在不介入再氧的情况下，缺氧（n = 4）对心脏没有保护作用（IS/AAR 50 +/- 8%；心律失常评分4.5 +/- 0.5；与间歇性缺氧相比P < 0.001）。因此，DOR、ROS和循环再氧化是间歇性缺氧产生的逐渐演变的心脏保护的必要参与者。
Intermittent, normobaric hypoxia confers robust cardioprotection against ischemia-induced myocardial infarction and lethal ventricular arrhythmias. delta-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) have been implicated in cardioprotective phenomena, but their roles in intermittent hypoxia are unknown. This study examined the contributions of DOR and ROS in mediating intermittent hypoxia-induced cardioprotection. Mongrel dogs completed a 20 day program consisting of 5-8 daily, 5-10 min cycles of moderate, normobaric hypoxia (FIO2 0.095-0.10), with intervening 4 min room air exposures. Subsets of dogs received the DOR antagonist naltrindole (200 mu g/kg, sc) or antioxidant N-acetylcysteine (250 mg/kg, po) before each hypoxia session. Twenty-four hours after the last session, the left anterior descending coronary artery was occluded for 60 min and then reperfused for 5 h. Arrhythmias detected by electrocardiography were scored according to the Lambeth II conventions. Left ventricles were sectioned and stained with 2,3,5-triphenyltetrazolium-chloride, and infarct sizes were expressed as percentages of the area at risk (IS/AAR). Intermittent hypoxia sharply decreased IS/AAR from 41 +/- 5 % (n = 12) to 1.8 +/- 0.9 % (n = 9; P < 0.001) and arrhythmia score from 4.1 +/- 0.3 to 0.7 +/- 0.2 (P < 0.001) vs. non-hypoxic controls. Naltrindole (n = 6) abrogated the cardioprotection with IS/AAR 35 +/- 5 % and arrhythmia score 3.7 +/- 0.7 (P < 0.001 vs. untreated intermittent hypoxia). N-acetylcysteine (n = 6) interfered to a similar degree, with IS/AAR 42 +/- 3 % and arrhythmia score 4.7 +/- 0.3 (P < 0.001 vs. untreated intermittent hypoxia). Without the intervening reoxygenations, hypoxia (n = 4) was not cardioprotective (IS/AAR 50 +/- 8 %; arrhythmia score 4.5 +/- 0.5; P < 0.001 vs. intermittent hypoxia). Thus DOR, ROS and cyclic reoxygenation were obligatory participants in the gradually evolving cardioprotection produced by intermittent hypoxia.