Neurovascular protection in voltage-gated proton channel Hv1 knock-out rats after ischemic stroke

interaction with Na+/H+ exchanger-1 antagonism

Weiguo Li, Rebecca Ward, Guangkuo Dong, Adviye Ergul, Paul M O'Connor

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere14142
JournalPhysiological reports
Volume7
Issue number13
DOIs
StatePublished - Jul 1 2019

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Sodium-Hydrogen Antiporter
Protons
Stroke
Middle Cerebral Artery Infarction
Reactive Oxygen Species
Wounds and Injuries
Inbred Dahl Rats
NADPH Oxidase
Microglia
Blood Vessels
Heart Diseases
Therapeutics
Ischemia
Macrophages
Clinical Trials
Mortality
Incidence
Proteins

Keywords

  • Ischemic stroke
  • NHE inhibitor
  • neurovascular protection
  • voltage-gated proton channel

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Neurovascular protection in voltage-gated proton channel Hv1 knock-out rats after ischemic stroke : interaction with Na+/H+ exchanger-1 antagonism. / Li, Weiguo; Ward, Rebecca; Dong, Guangkuo; Ergul, Adviye; O'Connor, Paul M.

In: Physiological reports, Vol. 7, No. 13, e14142, 01.07.2019.

Research output: Contribution to journalArticle

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