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一种水溶性一氧化碳释放分子的心脏保护作用。

Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule.

作者信息

Clark James E, Naughton Patrick, Shurey Sandra, Green Colin J, Johnson Tony R, Mann Brian E, Foresti Roberta, Motterlini Roberto

机构信息

Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, UK.

出版信息

Circ Res. 2003 Jul 25;93(2):e2-8. doi: 10.1161/01.RES.0000084381.86567.08. Epub 2003 Jul 3.

Abstract

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 micromol/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 micromol/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.

摘要

一氧化碳是哺乳动物体内血红素经血红素加氧酶降解过程中产生的一种重要信号介质。最近研究表明,过渡金属羰基化合物可作为一氧化碳释放分子(CO-RMs),并在生物系统中引发独特的药理活性。在本研究中,我们报告了一种水溶性CO-RM在体外和体内均具有心脏保护作用。具体而言,我们发现二氯(甘氨酸根)三羰基钌(II)(CORM-3)在酸性pH值的水中稳定,但在生理缓冲液中会迅速在溶液中释放CO。用CORM-3(10至50微摩尔/升)预处理的心脏细胞对缺氧复氧和氧化应激造成的损伤更具抵抗力。此外,缺血事件后在CORM-3(10微摩尔/升)存在下再灌注的离体心脏,心肌功能有显著恢复,心肌损伤和梗死面积明显显著减小。线粒体ATP依赖性钾通道抑制剂5-羟基癸酸可完全消除CORM-3在心脏细胞和离体心脏中介导的心脏保护作用。可以预见,当CORM-3被不能释放CO的无活性形式(iCORM-3)取代时,心脏保护作用丧失。使用小鼠心脏同种异体移植排斥模型,我们还发现用CORM-3而非iCORM-3治疗受体可显著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作为输送CO的载体这一观点,并突出了CO-RMs在减轻心脏功能障碍方面的生物活性和潜在治疗特性。本文全文可在http://www.circresaha.org在线获取。

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