Mechanism of Oxygen Free Radical-Induced Cellular Damage in Myocardium

氧自由基诱导心肌细胞损伤的机制

• 批准号: 63571102
• 负责人: OKABE Eiichiro
• 金额: $ 1.41万
• 依托单位: Kanagawa Dental College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1988
• 资助国家: 日本
• 起止时间: 1988 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-63571102/
• 关键词: Free Radical; Sarcoplasmic Reticulum; Calcium; Ischemia; Coronary Vessel; Calmodulin; 心筋虚血; 内皮細胞; フリーラジカル; 興奮-収縮連関; 筋鞘

We tested the hypothesis that oxygen free radical-induced breakdown in the function of sarcoplasmic reticulum (SR) and sarcolemma may serve as the source of intracellular calcium overload analogous to that seen in the ischemic myocardium, and extrapolated the in vitro results to the ischemic myocardium. The following results were obtained:1) Oxygen free radicals can produce a dininished level of accumulated calcium of SR, which is reflected by the decreased calcium load and an increase in calcium permeability, and the decreased calcium accumulation in the presence of oxygen free radical generating system may not be mainly due to an inhibited calcium pump. 2) Calmodulin-dependent component of calcium fluxes in SR vesicles is modified directly by oxygen free radicals, and oxygen free radicals can reduce steady-state calcium accumulation due to increased calcium release through a calcium efflux pathway which is inhibited by calmodulin. 3) Oxygen free radicals have no effect on myofibrilla … More r pCa-ATPase curve. 4) Oxygen free radicals reduce sarcolemmal Na^+, K^+ -ATPase activity and stimulate Na^+-Ca^<2+> exchange activity. 5) Oxygen free radicals produce endothelium-dependent and SOD inhibitable contraction of isolated left circumflex coronary arteries. 6) All these effects described above seem to be responsible for ^.O^-_ and/or closely related species of oxygen free radical, possibly ^.OH.The lack of an effect of oxygen free radicals may suggest that no structural alterations of contractile proteins have occurred. Thus, we would hypothesize that a major target organelles attacked by oxygen free radicals generated during the ischemic process is the portion of the excitation-contraction coupling system that regulates calcium delivery (the SR and sarcolemmal membrane) to the contractile proteins and not the contractile proteins per se. The SR calcium efflux pathways and sarcolemmal Na^+,K^+-ATPase involving Na^+-Ca^<2+> exchange activity may be altered by oxygen free radicals in ischemic myocardium where the occurrence of intracellular calcium overload plays an important role in cardiac dysfunction. Furthermore, it is postulated that oxygen free radicals participate in spasmogenesis in coronary vessels. Less

我们验证了氧自由基诱导的肌浆网（SR）和肌膜功能的破坏可能是细胞内钙超载的来源的假设，类似于缺血心肌的情况，并将体外实验结果推断为缺血心肌。结果表明：1)氧自由基可使SR的钙积累水平降低，表现为钙负荷降低，钙通透性增加，而在氧自由基生成系统存在的情况下，钙积累的减少可能主要不是由于钙泵受到抑制。2) SR囊泡中钙通量依赖钙调素的组分被氧自由基直接修饰，氧自由基通过钙外排途径增加钙释放，从而减少稳态钙积累，而钙外排途径被钙调素抑制。3)氧自由基对肌原纤维无明显影响。4)氧自由基降低肌层Na^+、K^+ - atp酶活性，刺激Na^+-Ca^<2+>交换活性。氧自由基引起离体左旋冠状动脉内皮依赖性和SOD抑制性收缩。以上所描述的所有这些影响似乎都是导致^的原因。O^-_和/或密切相关的氧自由基，可能是^. oh。缺乏氧自由基的作用可能表明没有发生收缩蛋白的结构改变。因此，我们假设缺血过程中产生的氧自由基攻击的主要靶细胞器是调节钙传递（SR和肌层膜）到收缩蛋白的兴奋-收缩耦合系统的一部分，而不是收缩蛋白本身。缺血心肌的SR钙外排通路和参与Na^+-Ca^<2+>交换活性的肌层Na^+，K^+- atp酶可能被氧自由基改变，细胞内钙超载的发生在心功能障碍中起重要作用。此外，假设氧自由基参与冠状血管的痉挛发生。少

项目成果

Okabe E: "Mechanisms of oxygen free radical-induced myocardial calcium overload." Ischemic Myocardium (Medical Tribune, Osaka), pp.4-5, 1988.

Okabe E：“氧自由基诱导心肌钙超载的机制。”

Okabe E, Ito H: "A permissive role for calcium efflux pathway, possibly a channel, in decreased calcium accumulation of cardiac sarcoplasmic reticulum induced by free radicals." Microcirc. ann. 4:37-38, 1989.

Okabe E、Ito H：“钙流出途径的许可作用，可能是自由基引起的心脏肌浆网钙积累减少的通道。”

Okabe E: "Review/Oxygen free radicals and myocardial injury." Circulation 10:17-22, 1989.

Okabe E：“回顾/氧自由基与心肌损伤。”

岡部栄逸郎: トキシコロジーフォーラム. 11. 595-609 (1988)

冈部荣一郎：毒理学论坛。11. 595-609 (1988)

Okabe E;Ito H.: Microcirculation an update. 1. 673-674 (1988)

Okabe E；Ito H.：微循环更新。