Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium
Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium
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DOI：
10.1016/j.cardiores.2005.11.004
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发表时间：
2006-02-01
影响因子：
10.8
通讯作者：
Galiñanes, M
中科院分区：
文献类型：
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作者：
Hassouna, A;Loubani, M;Galiñanes, M
目的：我们之前已经证明人类糖尿病心肌不能被预处理。在这里，我们研究了这种心脏保护缺陷的基础。 方法：来自四个患者组的右心房切片 - 非糖尿病、胰岛素依赖型糖尿病 (IDDM)、接受格列本脲的非胰岛素依赖型糖尿病 (NIDDM) 和接受二甲双胍的 NIDDM - 接受以下方案之一：有氧控制、 模拟缺血/复氧、缺血前的缺血预处理以及使用 α I 激动剂苯肾上腺素、腺苷、mito-K-ATP 通道开放剂二氮嗪、蛋白激酶 C (PKC) 激活剂佛波醇-12-肉豆蔻酸-13-乙酸酯 (PMA) 或 p38 丝裂原激活剂进行药理学预处理 蛋白激酶 (p38MAPK) 激活剂茴香霉素。使用肌酸激酶渗漏和 3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四唑 (MTT) 还原来评估细胞损伤。在非糖尿病和糖尿病心肌的线粒体制剂中，使用 JC-1 染料评估线粒体膜电位 (Psi(m))，并测定活性氧的产生。结果：用缺血、去氧肾上腺素、腺苷或二氮嗪进行预处理未能保护糖尿病心肌。然而，PKC 或 p38MAPK 的激活仍然具有保护作用。在分离的非糖尿病线粒体中，二氮嗪部分去极化 Psi(m)，这种作用在糖尿病线粒体中未见。此外，二氮嗪会增加非糖尿病患者的超氧化物产生，但不会增加糖尿病线粒体的超氧化物产生。结论：我们的结果表明，糖尿病心肌中的心脏保护缺陷出现在 PKC 和 p38MAPK 的上游。我们认为，糖尿病心肌中的线粒体功能障碍，可能是线粒体-K-ATP 通道功能障碍，导致去极化和超氧化物产生受损，从而导致无法对预处理做出反应。 (C) 2005 年欧洲心脏病学会。由 Elsevier B.V. 出版。保留所有权利。
Objectives: We have shown previously that human diabetic myocardium cannot be preconditioned. Here, we have investigated the basis of this cardioprotective deficit.Methods: Right atrial sections from four patient groups - non-diabetic, insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) receiving glibenclamide, and NIDDM receiving metformin-were subjected to one of the following protocols: aerobic control, simulated ischemia/reoxygenation, ischemic preconditioning before ischemia, and pharmacological preconditioning with alpha I agonist phenylephrine, adenosine, the mito-K-ATP channel opener diazoxide, the protein kinase C (PKC) activator phorbol-12-myristate- 13-acetate (PMA), or the p38 mitogen-activated protein kinase (p38MAPK) activator anisomycin. Cellular damage was assessed using creatine kinase leakage and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction. In mitochondrial preparations from non-diabetic and diabetic myocardium, mitochondrial membrane potential (Psi(m)) was assessed using JC-1 dye, and production of reactive oxygen species was determined.Results: Preconditioning with ischemia, phenylephrine, adenosine, or diazoxide failed to protect diabetic myocardium. However, activation of PKC or p38MAPK was still protective. In isolated non-diabetic mitochondria, diazoxide partially depolarized Psi(m), an effect not seen in diabetic mitochondria. Furthermore, diazoxide increased superoxide production in non-diabetic but not in diabetic mitochondria.Conclusions: Our results show that the cardioprotective deficit in diabetic myocardium arises upstream of PKC and p38MAPK. We suggest that mitochondrial dysfunction in diabetic myocardium, possibly dysfunctional mito-K-ATP channels, leads to impaired depolarization and superoxide production, and that this causes the inability to respond to preconditioning. (C) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.