Vascular and angiogenic activities of CORM-401, an oxidant-sensitive CO-releasing molecule
Vascular and angiogenic activities of CORM-401, an oxidant-sensitive CO-releasing molecule
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DOI：
10.1016/j.bcp.2015.12.014
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发表时间：
2016-02-15
影响因子：
5.8
通讯作者：
Foresti, Roberta
中科院分区：
文献类型：
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作者：
Fayad-Kobeissi, Sarah;Ratovonantenaina, Johary;Foresti, Roberta
一氧化碳（CO）由血红素加氧酶-1（HO-1）产生，并显示重要的信号传导、抗凋亡和抗炎活性，表明模拟其作用的药理学试剂可能具有治疗益处。本研究考察了CORM-401的生物化学和药理学性质，CORM-401是一种最近描述的含有锰作为金属中心的CO释放分子。我们使用体外方法，离体大鼠主动脉环和培养的EA.hy926内皮细胞系来解决CORM-401如何释放CO以及该化合物是否分别调节血管张力和促血管生成活性。我们发现，CORM-401释放高达三个CO/摩尔的化合物取决于受体肌红蛋白的浓度。氧化剂如H2O2、叔丁基过氧化氢或次氯酸增加CORM-401释放的CO。CORM-401还松弛预收缩的主动脉环，并且与H2O2组合增强血管舒张。与多个CO分子的释放一致，CORM-401诱导的血管舒张比CORM-A1引起的血管舒张高三倍，CORM-A1表现出与CORM-401相似的半衰期，但每摩尔化合物仅释放一个CO。此外，暴露于CORM-401的内皮细胞在细胞内积累CO，加速体外迁移并增加VEGF和IL-8水平。使用药理学抑制剂的研究显示HO-1和p38 MAP激酶是参与刺激迁移的两个独立和平行的机制。我们得出结论，CORM-401释放多种CO的能力，它对增加CO释放的氧化剂的敏感性，以及它的血管和促血管生成特性突出了CO释放分子设计的新进展，这些分子可以定制用于治疗炎症和氧化应激介导的病理学。(C)2015 Elsevier Inc. All rights reserved.
Carbon monoxide (CO) is generated by heme oxygenase-1 (HO-1) and displays important signaling, antiapoptotic and anti-inflammatory activities, indicating that pharmacological agents mimicking its action may have therapeutic benefit. This study examined the biochemical and pharmacological properties of CORM-401, a recently described CO-releasing molecule containing manganese as a metal center. We used in vitro approaches, ex-vivo rat aortic rings and the EA.hy926 endothelial cell line in culture to address how CORM-401 releases CO and whether the compound modulates vascular tone and pro-angiogenic activities, respectively. We found that CORM-401 released up to three CO/mole of compound depending on the concentration of the acceptor myoglobin. Oxidants such as H2O2,tert-butyl hydroperoxide or hypochlorous acid increased the CO liberated by CORM-401. CORM-401 also relaxed pre-contracted aortic rings and vasorelaxation was enhanced in combination with H2O2. Consistent with the release of multiple CO molecules, CORM-401-induced vasodilation was three times higher than that elicited by CORM-A1, which exhibits a similar half-life to CORM-401 but liberates only one CO/mole of compound. Furthermore, endothelial cells exposed to CORM-401 accumulated CO intracellularly, accelerated migration in vitro and increased VEGF and IL-8 levels. Studies using pharmacological inhibitors revealed HO-1 and p38 MAP kinase as two independent and parallel mechanisms involved in stimulating migration. We conclude that the ability of CORM-401 to release multiple CO, its sensitivity to oxidants which increase CO release, and its vascular and pro-angiogenic properties highlight new advances in the design of CO-releasing molecules that can be tailored for the treatment of inflammatory and oxidative stress-mediated pathologies. (C) 2015 Elsevier Inc. All rights reserved.