MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice
MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice
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DOI：
10.1182/blood-2013-02-486282
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发表时间：
2013-10-10
期刊：
影响因子：
20.3
通讯作者：
Vercellotti, Gregory M.
中科院分区：
文献类型：
--
作者：
Belcher, John D.;Young, Mark;Vercellotti, Gregory M.
表达β（S）血红蛋白的转基因镰状小鼠在多个器官中具有活化的血管内皮，其表现出NF-κ B和粘附分子的增强表达，并促进镰状小鼠中的微血管停滞，但对缺氧/再氧合（H/R）或血红素的反应不正常。诱导血红素加氧酶-1（HO-1）或给予其产物一氧化碳（CO）或胆绿素可抑制镰状小鼠的微血管淤滞。输注人血红蛋白与聚乙二醇结合并饱和CO（MP4 CO）可显著诱导镰状小鼠肝脏HO-1活性，并抑制NF-κ B活化和H/R诱导的微血管停滞。这些作用是由CO介导的;生理盐水或O-2饱和的MP4（MP4 OX）对H/R诱导的瘀滞几乎没有影响，尽管未修饰的氧合血红蛋白加剧了瘀滞。HO-1抑制剂锡原卟啉阻断了MP4 CO的保护作用，这与HO-1参与MP4 CO的保护作用一致。MP4 CO还诱导核因子-红细胞2 p45相关因子2（Nrf 2），这是HO-1和其他抗氧化基因的重要转录调节因子。在杂合子（血红蛋白-AS）镰状小鼠模型中，静脉注射氯化血红素在120分钟内诱导心血管衰竭和死亡，MP4 CO可显著降低心血管衰竭和死亡率，但MP4 OX不能。这些数据表明，在转基因镰状小鼠模型中，MP4 CO诱导细胞保护性Nrf 2和HO-1，并降低NF-κ B活化、微血管停滞和死亡率。
Transgenic sickle mice expressing beta(S) hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-kappa B and adhesion molecules and promotes microvascular stasis in sickle, but not normal, mice in response to hypoxia/reoxygenation (H/R), or heme. Induction of heme oxygenase-1 (HO-1) or administration of its products, carbon monoxide (CO) or biliverdin, inhibits microvascular stasis in sickle mice. Infusion of human hemoglobin conjugated with polyethylene glycol and saturated with CO (MP4CO) markedly induced hepatic HO-1 activity and inhibited NF-kappa B activation and H/R-induced microvascular stasis in sickle mice. These effects were mediated by CO; saline or MP4 saturated with O-2 (MP4OX) had little to no effect on H/R-induced stasis, though unmodified oxyhemoglobin exacerbated stasis. The HO-1 inhibitor, tin protoporphyrin, blocked MP4CO protection, consistent with HO-1 involvement in the protection afforded by MP4CO. MP4CO also induced nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), an important transcriptional regulator of HO-1 and other antioxidant genes. In a heterozygous (hemoglobin-AS) sickle mouse model, intravenous hemin induced cardiovascular collapse and mortality within 120 minutes, which was significantly reduced by MP4CO, but not MP4OX. These data demonstrate that MP4CO induces cytoprotective Nrf2 and HO-1 and decreases NF-kappa B activation, microvascular stasis, and mortality in transgenic sickle mouse models.