RGD Reference Report - Neurovascular protection in voltage-gated proton channel Hv1 knock-out rats after ischemic stroke: interaction with Na+ /H+ exchanger-1 antagonism. - Rat Genome Database

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Neurovascular protection in voltage-gated proton channel Hv1 knock-out rats after ischemic stroke: interaction with Na+ /H+ exchanger-1 antagonism.

Authors: Li, Weiguo  Ward, Rebecca  Dong, Guangkuo  Ergul, Adviye  O'Connor, Paul 
Citation: Li W, etal., Physiol Rep. 2019 Aug;7(13):e14142. doi: 10.14814/phy2.14142.
RGD ID: 14985213
Pubmed: PMID:31250553   (View Abstract at PubMed)
PMCID: PMC6597793   (View Article at PubMed Central)
DOI: DOI:10.14814/phy2.14142   (Journal Full-text)

Experimental studies have demonstrated protective effects of NHE-1 inhibition on cardiac function; however, clinical trials utilizing NHE-1 antagonists found an increase in overall mortality attributed to thromboembolic strokes. NADPH oxidase-derived reactive oxygen species (ROS) from microglial cells have been shown to contribute to injury following stroke. We have recently demonstrated that NHE-1 inhibition enhances ROS in macrophages in a Hv1-dependent manner. As Hv1 protein is highly expressed in microglia, we hypothesized that "NHE-1 inhibition may augment neurovascular injury by activating Hv1," providing a potential mechanism for the deleterious effects of NHE-1. The goal of this study was to determine whether neurovascular injury and functional outcomes after experimental stroke differed in wild-type and Hv1 mutant Dahl salt-sensitive rats treated with an NHE-1 inhibitor. Stroke was induced using both transient and permanent of middle cerebral artery occlusion (MCAO). Animals received vehicle or NHE-1 inhibitor KR32568 (2 mg/kg, iv) either 30 min after the start of MCAO or were pretreated (2 mg/kg, iv, day) for 3 days and then subjected to MCAO. Our data indicate that Hv1 deletion confers both neuronal and vascular protection after ischemia. In contrast to our hypothesis, inhibition of NHE-1 provided further protection from ischemic stroke, and the beneficial effects of both pre- and post-treatment with KR32568 were similar in wild-type and Hv1-/- rats. These data indicate that Hv1 activation is unlikely to be responsible for the increased incidence of cerebrovascular events observed in the heart disease patients after NHE-1 inhibition treatment.



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Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Hvcn1Ratcerebral edema  IMP  RGD 
Hvcn1em2McwiRatcerebral edema  IMP  RGD 
SS-Hvcn1em2Mcwi-/-Ratcerebral edema  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Hvcn1  (hydrogen voltage-gated channel 1)
Hvcn1em2Mcwi  (hydrogen voltage-gated channel 1; zinc finger nuclease induced mutant 2, Medical College of Wisconsin)
Slc9a1  (solute carrier family 9 member A1)

Genes (Mus musculus)
Hvcn1  (hydrogen voltage-gated channel 1)
Slc9a1  (solute carrier family 9 (sodium/hydrogen exchanger), member 1)

Genes (Homo sapiens)
HVCN1  (hydrogen voltage gated channel 1)
SLC9A1  (solute carrier family 9 member A1)

Strains
SS-Hvcn1em2Mcwi-/-  (NA)

Objects referenced in this article
Strain SS-Hvcn1em1Mcwi null Rattus norvegicus

Additional Information