Iron chelation with salicylaldehyde isonicotinoyl hydrazone protects against catecholamine autoxidation and cardiotoxicity
Iron chelation with salicylaldehyde isonicotinoyl hydrazone protects against catecholamine autoxidation and cardiotoxicity
复制标题
DOI：
10.1016/j.freeradbiomed.2010.12.004
复制
发表时间：
2011-02-15
影响因子：
7.4
通讯作者：
Simunek, Tomas
中科院分区：
文献类型：
--
作者：
Haskova, Pavlina;Kovarikova, Petra;Simunek, Tomas
已知升高的儿茶酚胺水平会引起心脏组织的损伤。这种儿茶酚胺心脏毒性可能源于它们经历氧化转化为氨基色素和伴随产生活性氧（ROS）的能力，活性氧通过铁催化的Fenton型反应损害心肌细胞。这表明铁螯合作用可能具有心脏保护作用。我们的体外实验表明，在缓冲溶液中预孵育24小时期间，儿茶酚胺、肾上腺素和异丙肾上腺素的浓度会自发降低，并逐渐转化为氧化产物。这些变化显着增加了铁离子和减少铁螯合剂水杨醛异烟酰腙（SIH）。氧化的儿茶酚胺与铁形成具有显着氧化还原活性的复合物，这可以被SIH抑制。使用H9c2成心肌细胞系的实验显示，氧化的儿茶酚胺比母体化合物的细胞毒性更高，显然是通过诱导半胱天冬酶非依赖性细胞死亡，而细胞与SIH的共孵育能够显着保持细胞活力。细胞内ROS形成的显着增加后，观察到细胞与儿茶酚胺氧化产物孵育，这可以显着减少SIH。与此相反，父母的儿茶酚胺并没有增加，而是减少，细胞的活性氧产生。因此，我们的研究结果表明，氧化还原活性铁在儿茶酚胺自氧化和随后的毒性的重要作用。铁螯合剂SIH通过抑制有害的儿茶酚胺氧化为活性中间体和预防ROS介导的心脏毒性，显示出相当大的保护心脏细胞的潜力。(C)2010年爱思唯尔公司All rights reserved.
Elevated catecholamine levels are known to induce damage of the cardiac tissue. This catecholamine cardiotoxicity may stem from their ability to undergo oxidative conversion to aminochromes and concomitant production of reactive oxygen species (ROS), which damage cardiomyocytes via the iron-catalyzed Fenton-type reaction. This suggests the possibility of cardioprotection by iron chelation. Our in vitro experiments have demonstrated a spontaneous decrease in the concentration of the catecholamines epinephrine and isoprenaline during their 24-h preincubation in buffered solution as well as their gradual conversion to oxidation products. These changes were significantly augmented by addition of iron ions and reduced by the iron-chelating agent salicylaldehyde isonicotinoyl hydrazone (SIH). Oxidized catecholamines were shown to form complexes with iron that had significant redox activity, which could be suppressed by SIH. Experiments using the H9c2 cardiomyoblast cell line revealed higher cytotoxicity of oxidized catecholamines than of the parent compounds, apparently through the induction of caspase-independent cell death, whereas co-incubation of cells with SIH was able to significantly preserve cell viability. A significant increase in intracellular ROS formation was observed after the incubation of cells with catecholamine oxidation products; this could be significantly reduced by SIH. In contrast, parent catecholamines did not increase, but rather decreased, cellular ROS production. Hence, our results demonstrate an important role for redox-active iron in catecholamine autoxidation and subsequent toxicity. The iron chelator SIH has shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity. (C) 2010 Elsevier Inc. All rights reserved.