Inhibition of overexpressed Kv3.4 augments HPV in endotoxemic mice

Maurizio Turzo,Cornelius J Busch,Karin Metzger,Felix Lasitschka,Markus A Weigand

doi:10.1186/s12890-020-01278-5

Maurizio Turzo, Cornelius J Busch + Show 3 more

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https://doi.org/10.1186/s12890-020-01278-5

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Abstract

BackgroundHypoxic pulmonary vasoconstriction (HPV) is a reaction of the pulmonary vasculature upon hypoxia, diverting blood flow into ventilated areas to preserve oxygenation. It is impaired in endotoxemia or ARDS. Voltage gated potassium channels have been shown to play a key role in the regulation of HPV. The aim of the study was to identify a voltage gated potassium channel involved in dysregulated HPV during endotoxemia.MethodsLungs of male C57BL/6 mice with and without endotoxemia (n = 6 ea. group) were analyzed for Kv3.4 gene and protein expression. HPV was examined in isolated perfused lungs of mice with and without endotoxemia and with and without selective Kv3.4 blocker BDS-I (n = 7 ea. group). Pulmonary artery pressure (PAP) and pressure-flow curves were measured during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation. HPV was quantified as the increase in perfusion pressure in response to hypoxia in percent of baseline perfusion pressure (ΔPAP) in the presence and absence of BDS-I.ResultsKv3.4 gene (3.2 ± 0.5-fold, p < 0.05) and protein (1.5 ± 0.1-fold p < 0.05) expression levels were increased in endotoxemic mouse lungs. Endotoxemia reduced HPV (∆PAP control: 121.2 ± 8.7% vs. LPS 19.5 ± 8.0%, means ± SEM) while inhibition of Kv3.4 with 50 nM BDS-I augmented HPV in endotoxemic but not in control lungs (∆PAP control BDS-I: 116.6 ± 16.0% vs. LPS BDS-I 84.4 ± 18.2%, means ± SEM).ConclusionsKv3.4 gene and protein expressions are increased in endotoxemic mouse lungs. Selective inhibition of Kv3.4 augments HPV in lungs of endotoxemic mice, but not in lungs of control mice.

Highlights

Hypoxic pulmonary vasoconstriction (HPV) is a reaction of the pulmonary vasculature upon hypoxia, diverting blood flow into ventilated areas to preserve oxygenation
We report that Kv3.4 gene as well as protein expressions were induced in endotoxemic mouse lungs
Endotoxemia increases pulmonary KCNC4 gene expression Extracts of total lung tissue from mice with LPS i.p. showed an increase of Kv3.4 gene expression (3.9 ± 0.5fold, n = 6, mean ± standard of error mean (SEM), p < 0.05) (Fig. 1) in comparison to 0.9% sodium chloride (NaCl) solution treated controls (1.0 ± 0.2-fold, normalized on 1, n = 6, means ± SEM)

Summary

Introduction

Hypoxic pulmonary vasoconstriction (HPV) is a reaction of the pulmonary vasculature upon hypoxia, diverting blood flow into ventilated areas to preserve oxygenation. It is impaired in endotoxemia or ARDS. Voltage gated potassium channels have been shown to play a key role in the regulation of HPV. Hypoxic pulmonary vasoconstriction (HPV) regulates pulmonary blood flow to match ventilation and optimize oxygenation [1]. HPV is diminished in humans and animals with pneumonia, sepsis or ARDS [2,3,4] This accounts for an increase of intrapulmonary shunt with subsequent hypoxia [1]. Kv3.4, Kv6.3 and Kv9.3 have been described as oxygen sensitive or as regulative subunits for Kv2.1 [1, 6,7,8,9]

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