Sulfated non-anticoagulant heparin derivative modifies intracellular hemoglobin, inhibits cell sickling in vitro, and prolongs survival of sickle cell mice under hypoxia.
Sulfated non-anticoagulant heparin derivative modifies intracellular hemoglobin, inhibits cell sickling in vitro, and prolongs survival of sickle cell mice under hypoxia.
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DOI：
10.3324/haematol.2020.272393
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发表时间：
2022-02-01
期刊：
影响因子：
10.1
通讯作者：
Mousa SA
中科院分区：
文献类型：
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作者：
Abdulmalik O;Darwish NHE;Muralidharan-Chari V;Taleb MA;Mousa SA
镰状细胞病（SCD）是一种由单点突变引起的常染色体隐性遗传病，导致镰状血红蛋白（HbS）异常。在缺氧或脱水期间，HbS聚合形成不溶性聚集体并诱导红细胞镰状化，这增加了细胞的粘附性，从而改变了血液的流变学性质，并引发炎症反应，导致溶血和血管闭塞性危象。普通肝素和低分子量肝素已被建议作为缓解SCD凝血并发症的治疗方法。然而，它们与重复给药后的出血并发症有关。先前报道了一种替代的硫酸化非抗凝肝素衍生物（S-NACH），其无全身抗凝活性至低全身抗凝活性，且无出血副作用，并且其干扰镰状细胞与内皮细胞的P-选择素依赖性结合，伴随SCD小鼠中粘附生物标志物水平的降低。S-NACH已被进一步工程化和结构增强以结合和修饰HbS以直接抑制镰状化，因此采用多模式方法。在这里，我们表明，S-NACH可以：（i）直接参与与HbS的希夫碱反应，以减少红细胞在体外常氧和缺氧条件下的镰状化，（ii）延长缺氧条件下SCD小鼠的存活时间，以及（iii）调节促炎和抗炎细胞因子的稳态水平。因此，我们的概念验证、体外和体内临床前研究表明，多模式S-NACH是一种非常有前途的候选药物，可开发为治疗SCD患者的低分子量肝素的改进和优化替代药物。
Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by a single point mutation, resulting in abnormal sickle hemoglobin (HbS). During hypoxia or dehydration, HbS polymerizes to form insoluble aggregates and induces sickling of red blood cells, which increases the adhesiveness of the cells, thereby altering the rheological properties of the blood, and triggers inflammatory responses, leading to hemolysis and vaso-occlusive crises. Unfractionated heparin and low-molecular weight heparins have been suggested as treatments to relieve coagulation complications in SCD. However, they are associated with bleeding complications after repeated dosing. An alternative sulfated non-anticoagulant heparin derivative (S-NACH) was previously reported to have no to low systemic anticoagulant activity and no bleeding side effects, and it interfered with P-selectin-dependent binding of sickle cells to endothelial cells, with concomitant decrease in the levels of adhesion biomarkers in SCD mice. S-NACH has been further engineered and structurally enhanced to bind with and modify HbS to inhibit sickling directly, thus employing a multimodal approach. Here, we show that S-NACH can: (i) directly engage in Schiff-base reactions with HbS to decrease red blood cell sickling under both normoxia and hypoxia in vitro, (ii) prolong the survival of SCD mice under hypoxia, and (iii) regulate the altered steady state levels of pro- and anti-inflammatory cytokines. Thus, our proof-of-concept, in vitro and in vivo preclinical studies demonstrate that the multimodal S-NACH is a highly promising candidate for development into an improved and optimized alternative to low-molecular weight heparins for the treatment of patients with SCD.
DOI：
10.1177/1076029620951851
发表时间：
2020-01
期刊：
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
影响因子：
--
作者：
Kouta A;Hoppensteadt D;Bontekoe E;Jeske W;Duff R;Cera L;Fareed J
通讯作者：
Fareed J