Nitric oxide reduces sickle hemoglobin polymerization: potential role of nitric oxide-induced charge alteration in depolymerization.
Nitric oxide reduces sickle hemoglobin polymerization: potential role of nitric oxide-induced charge alteration in depolymerization.
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DOI：
10.1016/j.abb.2011.03.013
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发表时间：
2011-06-01
影响因子：
3.9
通讯作者：
Head CA
中科院分区：
文献类型：
--
作者：
Ikuta T;Thatte HS;Tang JX;Mukerji I;Knee K;Bridges KR;Wang S;Montero-Huerta P;Joshi RM;Head CA
我们以前证明，吸入一氧化氮（NO）增加镰状细胞病（SCD）患者的镰状红细胞（RBC）的氧亲和力。我们最近的研究发现，NO降低了镰状血红蛋白（HbS）溶血产物的P50值，但没有增加高铁血红蛋白（metHb）水平，支持NO的作用，而不是metHb，在HbS的氧亲和力。在这里，我们研究了NO增加HbS氧亲和力的机制。因为抗镰状化剂增加镰状RBC氧亲和力，我们首先确定NO是否表现出抗镰状化特性。通过落球试验测量的HbS溶血产物的粘度在脱氧后增加; NO处理降低了增量。多光子显微镜分析表明，较小的HbS聚合物脱氧镰状红细胞和HbS溶血暴露于NO。这些结果表明，NO抑制HbS聚合物的形成，并具有抗镰状化特性。此外，我们发现用NO处理的HbS表现出与HbA相似的等电点，这表明NO改变了HbS的电荷。NO-HbS加合物在高效液相色谱分析中具有与HbA相同的洗脱时间。这项研究表明，NO可能会破坏HbS聚合物，通过消除过量的正电荷的HbS，导致增加的氧亲和力。
We previously demonstrated that inhaling nitric oxide (NO) increases the oxygen affinity of sickle red blood cells (RBCs) in patients with sickle cell disease (SCD). Our recent studies found that NO lowered the P50 values of sickle hemoglobin (HbS) hemolysates but did not increase methemoglobin (metHb) levels, supporting the role of NO, but not metHb, in the oxygen affinity of HbS. Here we examine the mechanism by which NO increases HbS oxygen affinity. Because anti-sickling agents increase sickle RBC oxygen affinity, we first determined whether NO exhibits anti-sickling properties. The viscosity of HbS hemolysates, measured by falling ball assays, increased upon deoxygenation; NO treatment reduced the increment. Multiphoton microscopic analyses showed smaller HbS polymers in deoxygenated sickle RBCs and HbS hemolysates exposed to NO. These results suggest that NO inhibits HbS polymer formation and has anti-sickling properties. Furthermore, we found that HbS treated with NO exhibits an isoelectric point similar to that of HbA, suggesting that NO alters the electric charge of HbS. NO–HbS adducts had the same elution time as HbA upon high performance liquid chromatography analysis. This study demonstrates that NO may disrupt HbS polymers by abolishing the excess positive charge of HbS, resulting in increased oxygen affinity.
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