title: The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke.
abstract: Phagocytic cell NADPH oxidase (NOX) generates reactive oxygen species (ROS) as part of innate immunity. Unfortunately, ischemia can also induce this pathway and inflict damage on native cells. The voltage-gated proton channel Hv1 enables NOX function by compensating cellular loss of electrons with protons. Accordingly, we investigated whether NOX-mediated brain damage in stroke can be inhibited by suppression of Hv1. We found that mouse and human brain microglia, but not neurons or astrocytes, expressed large Hv1-mediated currents. Hv1 was required for NOX-dependent ROS generation in brain microglia in situ and in vivo. Mice lacking Hv1 were protected from NOX-mediated neuronal death and brain damage 24 h after stroke. These results indicate that Hv1-dependent ROS production is responsible for a substantial fraction of brain damage at early time points after ischemic stroke and provide a rationale for Hv1 as a therapeutic target for the treatment of ischemic stroke.
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital Boston and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
authors.forename: Gongxiong
authors.initials: G
authors.lastname: Wu
authors.forename: M Reza
authors.initials: MR
authors.lastname: Akhavan Sharif
authors.forename: Amanda
authors.initials: A
authors.lastname: Baker
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jia
authors.forename: Frederic H
authors.initials: FH
authors.lastname: Fahey
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
authors.forename: Edward P
authors.initials: EP
authors.lastname: Feener
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000378:metabolism* / Q000473:pathology*
chemical_list: C510235:HVCN1 protein, human; C540876:Hv1 proton channel, mouse; D007473:Ion Channels; D017382:Reactive Oxygen Species