Mitochondrial adaptations within chronically ischemic swine myocardium
Mitochondrial adaptations within chronically ischemic swine myocardium
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DOI：
10.1016/j.yjmcc.2006.07.008
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发表时间：
2006-12-01
影响因子：
5
通讯作者：
Duncker, Dirk J.
中科院分区：
文献类型：
--
作者：
McFalls, Edward O.;Sluiter, Wim;Duncker, Dirk J.
实验证据表明，心肌缺血预处理可以使线粒体进入“应激抵抗状态”，从而减少长期严重缺血和再灌注后的细胞死亡。使用慢性缺血心肌的猪模型，我们测试了缺血区域内的线粒体也获得了保护性表型的假设。 11 头猪接受了左胸廓切开术，在近端左前降支 (LAD) 动脉周围放置了外缩器。 10 周时，通过定量冠状动脉造影记录 LAD 动脉严重狭窄 (92 +/- 2%)。从 LAD 和偏远地区处死动物并提取心肌。从 LAD 和偏远地区的心内膜下和心外膜下分离线粒体，并用 Clark 电极评估状态 2（仅基质）和状态 3（+ADP）呼吸。在LAD心内膜下，呼吸控制指数为2.68 +/- 0.17，低于远端心内膜下（3.64 +/- 0.08；P < 0.05）。当暴露于缺氧并再充氧 20 分钟时，与远程区域相比，LAD 区域表现出更保留的 3 态呼吸（分别为 99 +/- 14 与 65 +/- 9 nmol O-2/mg；P < 0.05）。在平行线粒体实验中，用探针腔肠素检测到化学发光，在抗霉素 A 存在的情况下，LAD 区域的超氧化物生成量为 574 +/- 108 RLU/30 s/mu g，比远程区域低近 50%（979 +/- 175 RLU/30 s/mu g；P < 0.05）。在线粒体内，与远端区域相比，Western 凝胶解偶联蛋白 (UCP) 2 的表达在 LAD 区域高出 20% (P < 0.05)，而 UCP-3 中没有差异。在这种慢性心肌缺血的猪模型中，从缺血组织中分离的线粒体表现出缺氧/复氧后保留的状态3呼吸，与应激抵抗状态一致。这种状态的特征是在基础条件下轻度解偶联和减少的超氧化物生成。线粒体中解偶联蛋白 2 的表达增强，为这些有利的线粒体适应提供了潜在机制。 (C) 2006 Elsevier Inc. 保留所有权利。
Experimental evidence has emerged that myocardial ischemic preconditioning can prime the mitochondria into a "stress-resistant state", so that cell death is reduced following prolonged severe ischemia and reperfusion. Using a swine model of chronically ischemic myocardium, we tested the hypothesis that mitochondria within the ischemic territory have also acquired a protective phenotype. Eleven swine underwent a left thoracotomy with placement of an external constrictor around the proximal left anterior descending (LAD) artery. By 10 weeks, a severe stenosis of the LAD artery was documented by quantitative coronary angiography (92 +/- 2%). Animals were sacrificed and myocardium was extracted from the LAD and remote regions. Mitochondria were isolated from subendocardium and subepicardium from LAD and remote regions and state 2 (substrate alone) and state 3 (+ADP) respiration were assessed with a Clark electrode. Within the LAD subendocardium, the respiratory control index was 2.68 +/- 0.17 and was lower than the remote subendocardium (3.64 +/- 0.08; P < 0.05). When exposed to 20 min anoxia with reoxygenation, the LAD region demonstrated a more preserved state 3 respiration compared with the remote region (99 +/- 14 versus 65 +/- 9 nmol O-2/mg, respectively; P < 0.05). In parallel mitochondrial experiments, chemiluminescence was detected with the probe coelenterazine and superoxide generation in the LAD region in the presence of antimycin A was 574 +/- 108 RLU/30 s/mu g and was nearly 50% lower than the remote region (979 +/- 175 RLU/30 s/mu g; P < 0.05). Within the mitochondria, the expression of uncoupling protein (UCP) 2 by western gels was 20% higher in the LAD region compared with the remote region (P < 0.05) with no differences noted in UCP-3. In this swine model of chronic myocardial ischemia, isolated mitochondria from the ischemic tissue demonstrate preserved state 3 respiration following anoxia/reoxygenation, consistent with a stress-resistant state. This state is characterized by a mild degree of uncoupling under basal conditions and decreased superoxide generation. Uncoupling protein 2 expression is enhanced in the mitochondria, providing a potential mechanism for these favorable mitochondrial adaptations. (C) 2006 Elsevier Inc. All rights reserved.