title: Increased brain hemopexin levels improve outcomes after intracerebral hemorrhage.
abstract: Following intracerebral hemorrhage (ICH), extracellular heme precipitates secondary brain injury, which results in irreversible brain damage and enduring neurological deficits. Hemopexin (Hpx) is an endogenous protein responsible for scavenging heme, thereby modulating its intrinsic proxidant/proinflammatory properties. Although Hpx is present in the brain, the endogenous levels are insufficient to combat the massive heme overload following ICH. We hypothesized that increasing brain Hpx levels would improve ICH outcomes. Unique recombinant adeno-associated viral vectors were designed to specifically overexpress Hpx within the mouse brain. Western blotting, ELISA, and immunohistochemistry of brain homogenates/sections, CSF, and serum were performed. As compared to controls, Hpx mice have increased Hpx protein levels in all three types of biospecimens evaluated, which results in 45.6 ± 6.9% smaller lesions and improved functional recovery after ICH (n=14-19/group, p < 0.05). Local mechanistic analyses show significantly less tissue injury, trends toward smaller hematoma volumes, unchanged heme oxygenase 1 and iron levels, and significantly increased microgliosis and decreased astrogliosis and lipid peroxidation. Peripheral levels of heme-related markers indicate a positive modulation of iron-binding capacity. These findings reveal that high local Hpx levels improve ICH outcomes, likely through both central and peripheral clearance mechanisms, and establish the potential for therapeutically administering clinical-grade Hpx for ICH.
authors.affiliation: 1 Department of Anesthesiology, University of Florida, Gainesville, FL, USA.|2 Department of Neuroscience, McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Leclerc
authors.affiliation: 1 Department of Anesthesiology, University of Florida, Gainesville, FL, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Santiago-Moreno
authors.affiliation: 1 Department of Anesthesiology, University of Florida, Gainesville, FL, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Dang
authors.affiliation: 1 Department of Anesthesiology, University of Florida, Gainesville, FL, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Lampert
authors.affiliation: 2 Department of Neuroscience, McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.
authors.forename: Pedro E
authors.initials: PE
authors.lastname: Cruz
authors.affiliation: 2 Department of Neuroscience, McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.
authors.forename: Awilda M
authors.initials: AM
authors.lastname: Rosario
authors.affiliation: 2 Department of Neuroscience, McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: 1 Department of Anesthesiology, University of Florida, Gainesville, FL, USA.|2 Department of Neuroscience, McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|3 Departments of Neurology, Psychology, Psychiatry, and Pharmaceutics, University of Florida, Gainesville, FL, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Doré
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000378:metabolism* / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006466:Hemopexin / Q000378:metabolism*; D015227:Lipid Peroxidation; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice
chemical_list: D015415:Biomarkers; D008565:Membrane Proteins; D006466:Hemopexin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Gliosis; hemorrhage; neuroinflammation; oxidative stress; stroke