Low-density lipoprotein receptor-related protein-1 facilitates heme scavenging after intracerebral hemorrhage in mice

Gaiqing Wang, Anatol Manaenko, Anwen Shao, Yibo Ou, Peng Yang, Enkhjargal Budbazar, Derek Nowrangi, John H. Zhang, Jiping Tang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1299-1310
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume37
Issue number4
DOIs
StatePublished - Apr 2017

ASJC Scopus Subject Areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Keywords

  • Blood-brain barrier permeability
  • Brain edema
  • Heme scavenging
  • Intracerebral hemorrhage
  • Low-density lipoprotein receptor-related protein-1
  • Neuroprotective Agents/administration & dosage
  • Heme/metabolism
  • Male
  • Recombinant Proteins
  • Capillary Permeability/drug effects
  • Mice, Inbred Strains
  • Animals
  • Hemopexin/metabolism
  • Receptors, LDL/administration & dosage
  • Behavior, Animal/drug effects
  • Blood-Brain Barrier/drug effects
  • Cerebral Hemorrhage/drug therapy
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Tumor Suppressor Proteins/administration & dosage

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