Wang Gaiqing, Manaenko Anatol, Shao Anwen, Ou Yibo, Yang Peng, Budbazar Enkhjargal, Nowrangi Derek, Zhang John H, Tang Jiping
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
2 Department of Neurology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
J Cereb Blood Flow Metab. 2017 Apr;37(4):1299-1310. doi: 10.1177/0271678X16654494. Epub 2016 Jan 1.
Heme-degradation after erythrocyte lysis plays an important role in the pathophysiology of intracerebral hemorrhage. Low-density lipoprotein receptor-related protein-1 is a receptor expressed predominately at the neurovascular interface, which facilitates the clearance of the hemopexin and heme complex. In the present study, we investigated the role of low-density lipoprotein receptor-related protein-1 in heme removal and neuroprotection in a mouse model of intracerebral hemorrhage. Endogenous low-density lipoprotein receptor-related protein-1 and hemopexin were increased in ipsilateral brain after intracerebral hemorrhage, accompanied by increased hemoglobin levels, brain water content, blood-brain barrier permeability and neurological deficits. Exogenous human recombinant low-density lipoprotein receptor-related protein-1 protein reduced hematoma volume, brain water content surrounding hematoma, blood-brain barrier permeability and improved neurological function three days after intracerebral hemorrhage. The expression of malondialdehyde, fluoro-Jade C positive cells and cleaved caspase 3 was increased three days after intracerebral hemorrhage in the ipsilateral brain tissues and decreased with recombinant low-density lipoprotein receptor-related protein-1. Intracerebral hemorrhage decreased and recombinant low-density lipoprotein receptor-related protein-1 increased the levels of superoxide dismutase 1. Low-density lipoprotein receptor-related protein-1 siRNA reduced the effect of human recombinant low-density lipoprotein receptor-related protein-1 on all outcomes measured. Collectively, our findings suggest that low-density lipoprotein receptor-related protein-1 contributed to heme clearance and blood-brain barrier protection after intracerebral hemorrhage. The use of low-density lipoprotein receptor-related protein-1 as supplement provides a novel approach to ameliorating intracerebral hemorrhage brain injury via its pleiotropic neuroprotective effects.
红细胞裂解后的血红素降解在脑出血的病理生理学中起重要作用。低密度脂蛋白受体相关蛋白1是一种主要在神经血管界面表达的受体，它有助于清除血红素结合蛋白和血红素复合物。在本研究中，我们在脑出血小鼠模型中研究了低密度脂蛋白受体相关蛋白1在血红素清除和神经保护中的作用。脑出血后同侧脑内内源性低密度脂蛋白受体相关蛋白1和血红素结合蛋白增加，同时血红蛋白水平、脑含水量、血脑屏障通透性和神经功能缺损也增加。外源性人重组低密度脂蛋白受体相关蛋白1蛋白可减少脑出血后三天的血肿体积、血肿周围脑含水量、血脑屏障通透性，并改善神经功能。脑出血后三天同侧脑组织中丙二醛、氟玉髓C阳性细胞和裂解的半胱天冬酶3的表达增加，而重组低密度脂蛋白受体相关蛋白1可使其降低。脑出血可降低超氧化物歧化酶1的水平，而重组低密度脂蛋白受体相关蛋白1可使其升高。低密度脂蛋白受体相关蛋白1 siRNA降低了人重组低密度脂蛋白受体相关蛋白1对所有测量结果的影响。总体而言，我们的研究结果表明，低密度脂蛋白受体相关蛋白1有助于脑出血后的血红素清除和血脑屏障保护。使用低密度脂蛋白受体相关蛋白1作为补充剂，通过其多效性神经保护作用，为改善脑出血性脑损伤提供了一种新方法。
