Apohemoglobin-haptoglobin complex attenuates the pathobiology of circulating acellular hemoglobin and heme.
Apohemoglobin-haptoglobin complex attenuates the pathobiology of circulating acellular hemoglobin and heme.
复制标题
脱辅基血红蛋白-触珠蛋白复合物减弱循环无细胞血红蛋白和血红素的病理学。
DOI：
10.1152/ajpheart.00136.2020
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Cabrales,Pedro
中科院分区：
文献类型：
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作者：
Munoz,CarlosJ;Pires,IvanS;Baek,JinHyen;Buehler,PaulW;Palmer,AndreF;Cabrales,Pedro
触珠蛋白（Hp）是结合和清除无细胞血红蛋白（Hb）的血浆蛋白，而脱辅基血红蛋白（apoHb，即，血红蛋白缺乏血红素）可以结合血红素。因此，apoHb-Hp蛋白复合物应促进holoHb-apoHb αβ-二聚体交换和apoHb-血红素嵌入。因此，我们假设apoHb-Hp可以促进Hb和血红素的清除，如果不减轻，可能会有严重的微循环后果。在这项研究中，我们的特点apoHb-Hp和Hb/血红素配体相互作用，并评估其在体内的后果。采用体积排阻高效液相色谱法结合紫外可见分光光度法研究了血红蛋白交换和血红素与apoHb-Hp复合物的结合。在给予Hb或血红素-白蛋白的豚鼠中进行交换/转移实验，然后用等摩尔量的apoHb-Hp进行激发。最后，全身和微循环参数进行了研究，在仓鼠配备背窗室通过活体显微镜。体外和体内Hb交换和血红素转移实验证明了Hb/血红素配体转移至apoHb-Hp的概念验证。给予apoHb-Hp复合物逆转Hb和血红素诱导的全身性高血压和微血管收缩，减少微血管血流量，并减少功能性毛细血管密度。因此，这项研究强调了apoHb-Hp复合物作为一种新的治疗策略，以减轻不良的全身和微血管反应，血管内血红蛋白和血红素exposure.NEW和值得注意的是这项研究强调了apoHb-Hp复合物作为一种新的治疗策略，以减轻不良的全身和微血管反应，血管内血红蛋白和血红素exposure。体外和体内Hb交换和血红素转移实验证明了Hb/血红素配体转移至apoHb-Hp的概念验证。apoHb-Hp复合物逆转Hb和血红素诱导的全身性高血压和微血管收缩，保持微血管血流和功能性毛细血管密度。总之，apoHb-Hp复合物的独特性质防止了对Hb和血红素-白蛋白暴露的不良全身和微血管反应，并引入了一种新的治疗方法来促进细胞外Hb和血红素的同时去除。
Haptoglobin (Hp) is the plasma protein that binds and clears cell-free hemoglobin (Hb), whereas apohemoglobin (apoHb, i.e., Hb devoid of heme) can bind heme. Therefore, the apoHb-Hp protein complex should facilitate holoHb-apoHb αβ-dimer exchange and apoHb-heme intercalation. Thus, we hypothesized that apoHb-Hp could facilitate both Hb and heme clearance, which, if not alleviated, could have severe microcirculatory consequences. In this study, we characterized apoHb-Hp and Hb/heme ligand interactions and assessed their in vivo consequences. Hb exchange and heme binding with the apoHb-Hp complex was studied with transfer assays using size-exclusion high-performance liquid chromatography coupled with UV-visible spectrophotometry. Exchange/transfer experiments were conducted in guinea pigs dosed with Hb or heme-albumin followed by a challenge with equimolar amounts of apoHb-Hp. Finally, systemic and microcirculatory parameters were studied in hamsters instrumented with a dorsal window chamber via intravital microscopy. In vitro and in vivo Hb exchange and heme transfer experiments demonstrated proof-of-concept Hb/heme ligand transfer to apoHb-Hp. Dosing with the apoHb-Hp complex reversed Hb- and heme-induced systemic hypertension and microvascular vasoconstriction, reduced microvascular blood flow, and diminished functional capillary density. Therefore, this study highlights the apoHb-Hp complex as a novel therapeutic strategy to attenuate the adverse systemic and microvascular responses to intravascular Hb and heme exposure.NEW & NOTEWORTHYThis study highlights the apoHb-Hp complex as a novel therapeutic strategy to attenuate the adverse systemic and microvascular responses to intravascular Hb and heme exposure. In vitro and in vivo Hb exchange and heme transfer experiments demonstrated proof-of-concept Hb/heme ligand transfer to apoHb-Hp. The apoHb-Hp complex reverses Hb- and heme-induced systemic hypertension and microvascular vasoconstriction, preserves microvascular blood flow, and functional capillary density. In summary, the unique properties of the apoHb-Hp complex prevent adverse systemic and microvascular responses to Hb and heme-albumin exposure and introduce a novel therapeutic approach to facilitate simultaneous removal of extracellular Hb and heme.