The Mechanism of Proinflammatory HDL Generation in Sickle Cell Disease Is Linked to Cell-Free Hemoglobin via Haptoglobin.
The Mechanism of Proinflammatory HDL Generation in Sickle Cell Disease Is Linked to Cell-Free Hemoglobin via Haptoglobin.
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DOI：
10.1371/journal.pone.0164264
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gao H
中科院分区：
文献类型：
--
作者：
Ji X;Feng Y;Tian H;Meng W;Wang W;Liu N;Zhang J;Wang L;Wang J;Gao H
在镰状细胞病 (SCD) 中，高密度脂蛋白 (HDL) 的炎症特性可能会被溶血过程中释放到血液中的游离血红蛋白 (Hb) 改变。 SCD患者或小鼠血浆中的Hb可以与HDL结合，特异性诱导炎症反应。在我们的研究中，我们发现SCD慢性氧化状态下炎症因子蛋白含量增加，HDL载脂蛋白A-I (ApoA-1)颗粒中Hb、触珠蛋白(Hp)和血红素结合蛋白(Hx)水平较高，HDL的作用从抗炎变为促炎。我们的结果还表明，Hp 和 Hx（HDL 中 Hb 的清除剂）与 SCD 患者的炎症水平呈正相关。 HDL 在 Hp−/− 小鼠中保留了其炎症抑制作用，且 Hb 积累较少。 Hx可以进一步预防炎症反应，因为缺乏Hx时其水平会更高。因此，我们证明Hp在Hb与HDL结合并发挥明显促炎作用的过程中是不可或缺的。因此，必须打破Hb和Hp之间的结合来进行治疗。 Hb/Hp/Hx 复合物的解离也可能在其他炎症血管生成相关疾病的研究中发挥重要作用。
In sickle cell disease (SCD), the inflammatory properties of high-density lipoprotein (HDL) can be changed by cell-free hemoglobin (Hb), which is released into the blood during hemolysis. Hb in the plasma of SCD patients or mice can bind with HDL specifically inducing an inflammatory reaction. In our study, we found increased amounts of inflammatory factor proteins in the chronic oxidative state of SCD with higher levels of Hb, haptoglobin (Hp) and hemopexin (Hx) in the apolipoprotein A-I (ApoA-1) particles of HDL and the role of HDL is changed from being anti-inflammatory to proinflammatory. Our results also suggest Hp and Hx, the scavengers of Hb in HDL, are positively associated with inflammatory levels in SCD patients. HDL retained its inflammatory inhibition role in Hp−/− mice, with less Hb accumulation. Hx may further prevent inflammatory reaction because its level will be even higher when lack of Hx. We therefore demonstrated that Hp is indispensable during the process whereby Hb associates with HDL and plays a clear proinflammatory role. Therefore, it is essential to break the binding between Hb and Hp for treatment. The dissociation of Hb/Hp/Hx complexes may also play an important role in the study of other inflammatory angiogenesis-related diseases.
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