Impaired vasodilation by red blood cells in sickle cell disease
Impaired vasodilation by red blood cells in sickle cell disease
复制标题
DOI：
10.1073/pnas.0409876102
复制
发表时间：
2005-02-15
影响因子：
11.1
通讯作者：
Stamler, JS
中科院分区：
文献类型：
--
作者：
Pawloski, JR;Hess, DT;Stamler, JS
红细胞（RBC）在血管扩张中发挥着独特的作用，这需要o -2调节的结合和Hb对NO的生物激活，并将NO当量转移到RBC膜上。缺氧组织中的血管闭塞是镰状细胞性贫血的标志。在这里，我们发现镰状细胞Hb变异S （HbS）既缺乏从血红素铁（亚硝基铁，FeNO）到维持生物活性的半胱氨酸硫醇（S-亚硝基硫醇，SNO）的分子内NO转移，也缺乏从S-亚硝基血红蛋白（SNO-HbS）到红细胞膜的NO转移。因此，镰状红细胞缺乏膜SNO，其介导缺氧血管舒张的能力受损。此外，这些损伤的程度与疾病的临床严重程度相关。因此，我们的研究结果表明，红细胞血管活性异常有助于镰状细胞性贫血的血管闭塞性病理生理，而镰状细胞性贫血基因型表达的表型变异可能部分地解释为红细胞处理NO的可变缺陷。更一般地说，我们的发现提出了一氧化氮加工缺陷可能是一类新的血红蛋白病的特征。
Red blood cells (RBCs) have been ascribed a unique role in dilating blood vessels, which requires O-2-regulated binding and bioactivation of NO by Hb and transfer of NO equivalents to the RBC membrane. Vasoocclusion in hypoxic tissues is the hallmark of sickle cell anemia. Here we show that sickle cell Hb variant S (HbS) is deficient both in the intramolecular transfer of NO from heme iron (iron nitrosyl, FeNO) to cysteine thiol (S-nitrosothiol, SNO) that subserves bioactivation, and in transfer of the NO moiety from S-nitrosohemoglobin (SNO-HbS) to the RBC membrane. As a result, sickle RBCs are deficient in membrane SNO and impaired in their ability to mediate hypoxic vasodilation. Further, the magnitudes of these impairments correlate with the clinical severity of disease. Thus, our results suggest that abnormal RBC vasoactivity contributes to the vasoocclusive pathophysiology of sickle cell anemia, and that the phenotypic variation in expression of the sickle genotype may be explained, in part, by variable deficiency in RBC processing of NO. More generally, our findings raise the idea that defective NO processing may characterize a new class of hemoglobinopathy.