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JBC:脱氧血红蛋白研究助力红细胞疾病治疗
发布时间:2014-12-16 08:43 来源:未知

(Biofriend 转自 生物谷)近日,刊登在国际杂志Journal of Biological Chemistry上的一篇研究论文中,来自维克森林大学(Wake Forest)的研究人员通过研究揭示,脱氧血红蛋白的确可以诱发亚硝酸盐转化为一氧化氮,该过程往往会影响血流和机体的凝血。

研究者Kim-Shapiro说道,红细胞中由脱氧血红蛋白介导的亚硝酸盐向一氧化氮的转化会减少血小板的活化,这或许可以帮助开发新型疗法来减少镰刀形细胞病及中风患者机体的凝血。早在2003年研究者就发现亚硝酸盐并不像我们认为的那样具有生物惰性,其可以被转化成为机体重要的一氧化氮信号分子,从而增加血流,而如今研究者证实了他们之前的研究结论。

这项研究的目的在于揭示红细胞如何发挥自己重要的信号功能来增加机体的血流,研究者利用多种生物物理技术测定了来自亚硝酸盐和红细胞产生的一氧化氮的含量,并且分析了一氧化氮产生的分子机制;更为重要的是一氧化氮的产生水平可以在低氧状态下增加。随后研究人员通过研究揭示了亚硝酸盐及其生物前体-硝酸盐如何用于治疗一系列的人类疾病。

在2010年的研究中,研究者首次揭示了富含硝酸盐的甜菜汁中消耗和大脑血流的增加直接相关;最后研究者表示,下一步我们将进行更为深入的研究来揭示是否所有的红细胞都可以具有这种转化活性,以及是否该功能在诸如镰刀形细胞病等其它红细胞疾病中是处于缺失状态的。
 

Mechanisms of Human Erythrocytic Bioactivation of Nitrite.

Chen Liu1, Nadeem Wajih2, Xiaohua Liu1, Swati Basu1, John Janes1, Madison Marvel1, Christian Keggi1, Christine C. Helms3, Amber N. Lee1, Andrea M. Belanger1, Debra I. Diz1, Paul Laurienti1, David L. Caudell1, Jun Wang4, Mark T. Gladwin4 and Daniel B. Kim-Shapiro1*

 

Nitrite signaling likely occurs through its reduction to nitric oxide (NO). Several reports support a role of erythrocytes and hemoglobin in nitrite reduction, but this remains controversial and alternative reductive pathways have been proposed. In this work we determined whether the primary human erythrocytic nitrite reductase is hemoglobin as opposed to other erythrocytic proteins that have been suggested to be the major source of nitrite reduction. We employed several different assays to determine NO production from nitrite in erythrocytes including electron paramagnetic resonance detection of nitrosyl hemoglobin, chemiluminescent detection of NO, and inhibition of platelet activation and aggregation. Our studies show that NO is formed by red blood cells and inhibits platelet activation. Nitric oxide formation and signaling can be recapitulated with isolated deoxyhemoglobin. Importantly, there is limited NO production from erythrocytic xanthine oxidoreductase and nitric oxide synthase. Under certain conditions we find dorzolamide (an inhibitor of carbonic anhydrase) results in diminished nitrite bioactivation, but the role of carbonic anhydrase is abrogated when physiological concentrations of CO2 are present. Importantly, carbon monoxide, which inhibits hemoglobin function as a nitrite reductase, abolishes nitrite bioactivation. Overall our data suggest that deoxyhemoglobin is the primary erythrocytic nitrite reductase operating under physiological conditions and accounts for nitrite-mediated NO signaling in blood.