Faculty of Pharmacy, Charles University in Prague, 500 05 Hradec Králové, Czech Republic.
Free Radic Biol Med. 2011 Feb 15;50(4):537-49. doi: 10.1016/j.freeradbiomed.2010.12.004. Epub 2010 Dec 13.
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.
已知升高的儿茶酚胺水平可导致心脏组织损伤。这种儿茶酚胺的心脏毒性可能源于其发生氧化转化为氨基查耳酮和伴随产生的活性氧（ROS）的能力，ROS 通过铁催化的芬顿型反应损伤心肌细胞。这提示了通过铁螯合进行心脏保护的可能性。我们的体外实验已经证明，儿茶酚胺肾上腺素和异丙肾上腺素在缓冲溶液中孵育 24 小时的过程中，其浓度会自发下降，并且逐渐转化为氧化产物。添加铁离子会显著增强这些变化，而铁螯合剂水杨酸异烟酰腙（SIH）会降低这些变化。已证明氧化儿茶酚胺与铁形成具有显著氧化还原活性的复合物，而 SIH 可抑制这种活性。使用 H9c2 心肌细胞系的实验表明，氧化儿茶酚胺比母体化合物具有更高的细胞毒性，显然是通过诱导细胞凋亡的细胞死亡，而细胞与 SIH 共孵育则能够显著维持细胞活力。在用儿茶酚胺氧化产物孵育细胞后，观察到细胞内 ROS 形成显著增加；而 SIH 可显著减少这种增加。相比之下，母体儿茶酚胺不会增加而是降低细胞内的 ROS 产生。因此，我们的结果表明，氧化还原活性铁在儿茶酚胺自动氧化及其随后的毒性中起着重要作用。铁螯合剂 SIH 通过抑制有害儿茶酚胺氧化为活性中间体以及预防 ROS 介导的心脏毒性，显示出保护心脏细胞的巨大潜力。
