Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule
Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule
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DOI：
10.1161/01.res.0000084381.86567.08
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发表时间：
2003-07-25
影响因子：
20.1
通讯作者：
Motterlini, R
中科院分区：
文献类型：
--
作者：
Clark, JE;Naughton, P;Motterlini, R
一氧化碳是哺乳动物体内血红素氧合酶降解血红素过程中产生的一种重要的信号介质。过渡金属羰基化合物作为一氧化碳释放分子（CO-RM）在生物系统中具有独特的药理活性。在本研究中，我们报告了一种水溶性形式的CO-RM在体外和体内促进心脏保护作用。具体而言，我们发现，三羰基氯（甘氨酸）钌（II）（CORM-3）是稳定的，在酸性pH值的水，但在生理缓冲液中迅速释放CO的溶液。CORM-3（10 ~ 50 mumol/L）预处理的心肌细胞对缺氧-复氧和氧化应激引起的损伤具有更强的抵抗力。此外，在缺血事件后，在CORM-3（10 μ mol/L）的存在下再灌注的离体心脏显示心肌性能的显著恢复和心肌损伤和梗死面积的显著和显著减少。CORM-3介导的心肌保护作用在心肌细胞和离体心脏中被线粒体ATP依赖性钾通道抑制剂5-羟基癸酸完全消除。可以预见的是，当CORM-3被一种不能释放CO的非活性形式（iCORM-3）取代时，心脏保护作用就会丧失。使用小鼠心脏同种异体移植排斥模型，我们还发现，用CORM-3而不是iCORM-3治疗受体可以大大延长移植心脏的存活率。这些数据证实了过渡金属羰基化合物可用作输送CO的载体的观点，并强调了CO-RM在缓解心功能障碍方面的生物活性和潜在治疗特征。这篇文章的全文可以在http://www.circresaha.org上找到。
Carbon monoxide, which is generated in mammals during the degradation of heme by the enzyme heme oxygenase, is an important signaling mediator. Transition metal carbonyls have been recently shown to function as carbon monoxide-releasing molecules (CO-RMs) and to elicit distinct pharmacological activities in biological systems. In the present study, we report that a water-soluble form of CO-RM promotes cardioprotection in vitro and in vivo. Specifically, we found that tricarbonylchloro(glycinato) ruthenium(II) (CORM-3) is stable in water at acidic pH but in physiological buffers rapidly liberates CO in solution. Cardiac cells pretreated with CORM-3 (10 to 50 mumol/L) become more resistant to the damage caused by hypoxia-reoxygenation and oxidative stress. In addition, isolated hearts reperfused in the presence of CORM-3 (10 mumol/L) after an ischemic event displayed a significant recovery in myocardial performance and a marked and significant reduction in cardiac muscle damage and infarct size. The cardioprotective effects mediated by CORM-3 in cardiac cells and isolated hearts were totally abolished by 5-hydroxydecanoic acid, an inhibitor of mitochondrial ATP-dependent potassium channels. Predictably, cardioprotection is lost when CORM-3 is replaced by an inactive form (iCORM-3) that is incapable of liberating CO. Using a model of cardiac allograft rejection in mice, we also found that treatment of recipients with CORM-3 but not iCORM-3 considerably prolonged the survival rate of transplanted hearts. These data corroborate the notion that transition metal carbonyls could be used as carriers to deliver CO and highlight the bioactivity and potential therapeutic features of CO-RMs in the mitigation of cardiac dysfunction. The full text of this article is available online at http://www.circresaha.org.