Low-density lipoprotein receptor-related protein-1 facilitates heme scavenging after intracerebral hemorrhage in mice.
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.
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.|2 Department of Neurology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
Gaiqing
G
Wang
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
Anatol
A
Manaenko
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
Anwen
A
Shao
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
Yibo
Y
Ou
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
Peng
P
Yang
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
Enkhjargal
E
Budbazar
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
Derek
D
Nowrangi
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.|3 Department of Anesthesiology, Loma Linda University, Loma Linda, CA, USA.
John H
JH
Zhang
1 Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
Jiping
J
Tang
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006466:Hemopexin / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011973:Receptors, LDL / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D018696:Neuroprotective Agents; D011973:Receptors, LDL; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D006418:Heme; D006466:Hemopexin
Intracerebral hemorrhage; blood–brain barrier permeability; brain edema; heme scavenging; low-density lipoprotein receptor-related protein-1