Nielsen Vance G, Abeyta Anthony R
Department of Anesthesiology, The University of Arizona College of Medicine, Tucson, AZ 85724, USA.
Ross University School of Medicine, Bridgetown BB11037, Barbados.
Int J Mol Sci. 2025 Apr 10;26(8):3567. doi: 10.3390/ijms26083567.
The discovery of carbon monoxide releasing molecules (CORMs) was one of the most impactful innovations in biochemistry, affecting multiple disciplines for the past few decades. Sixteen years ago, a ruthenium dimer-containing CORM, CORM-2, enhanced coagulation and diminished fibrinolysis in human plasma by modulation of fibrinogen, plasmin, and α-antiplasmin via CO binding to putative heme groups attached to these proteins. This finding linked CO exposure in settings involving heme oxygenase-1 upregulation during inflammation or environmental exposure to thromboembolic disease in hundreds of subsequent manuscripts. However, CO-independent effects of CORM-2 involving a putative ruthenium radical (Ru•) formed during CO release was found to be responsible for many of effects by CORM-2 in other works. Using a novel approach with human plasmatic coagulation kinetic methods, Ru• was posited to bind to critical histidines and other amino acids to modulate function, and excess histidine to quench CORM-2-mediated effects. This paradigm of histidine addition would definitively address if CO or Ru• was responsible for CORM-2-mediated effects. Thus, plasma coagulation/fibrinolytic kinetic data were assessed via thrombelastography ±CORM-2, ±histidine added. Histidine nearly completely abrogated CORM-2-mediated hypercoagulation in a concentration-dependent fashion; further, histidine also nearly eliminated all kinetic effects on fibrinolysis. In conclusion, CORM-2 Ru• formation, not CO release, is the true molecular mechanism modulating coagulation and fibrinolysis.
一氧化碳释放分子（CORMs）的发现是生物化学领域最具影响力的创新之一，在过去几十年中影响了多个学科。十六年前，一种含钌二聚体的CORM，即CORM-2，通过一氧化碳与附着在这些蛋白质上的假定血红素基团结合，调节纤维蛋白原、纤溶酶和α-抗纤溶酶，从而增强人体血浆中的凝血作用并减少纤维蛋白溶解。这一发现将炎症期间血红素加氧酶-1上调或环境暴露情况下的一氧化碳暴露与随后数百篇手稿中提到的血栓栓塞性疾病联系起来。然而，在其他研究中发现，CORM-2的一些作用是由一氧化碳释放过程中形成的假定钌自由基（Ru•）介导的，与一氧化碳无关。采用一种新的人体血浆凝血动力学方法，推测Ru•与关键组氨酸和其他氨基酸结合以调节功能，并且过量的组氨酸会消除CORM-2介导的作用。添加组氨酸的这种模式将明确确定是一氧化碳还是Ru•导致了CORM-2介导的作用。因此，通过血栓弹力图评估血浆凝血/纤维蛋白溶解动力学数据，分别添加或不添加CORM-2和组氨酸。组氨酸以浓度依赖的方式几乎完全消除了CORM-2介导的高凝状态；此外，组氨酸也几乎消除了对纤维蛋白溶解的所有动力学影响。总之，调节凝血和纤维蛋白溶解的真正分子机制是CORM-2的Ru•形成，而非一氧化碳释放。
