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Publications
Publication
Neurovascular protection in voltage-gated proton channel Hv1 knock-out rats
after ischemic stroke: interaction with Na+ /H+ exchanger-1 antagonism.
Authors
Li W, Ward R, Dong G, Ergul A, O'Connor P
Submitted By
Weiguo Li on 8/2/2019
Status
Published
Journal
Physiological reports
Year
2019
Date Published
Volume : Pages
7 : e14142
PubMed Reference
31250553
Abstract
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.
Investigators with authorship
Name
Institution
Weiguo Li
Medical University of South Carolina
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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