Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders

Abstract Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the...

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Autores principales: Vassilios J. Bezzerides, Aifeng Zhang, Ling Xiao, Bridget Simonson, Santosh A. Khedkar, Shiro Baba, Filomena Ottaviano, Stacey Lynch, Katherine Hessler, Alan C. Rigby, David Milan, Saumya Das, Anthony Rosenzweig
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Publicado: Nature Portfolio 2017
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spelling oai:doaj.org-article:9af9999edb46428491a8bdbba7942bc42021-12-02T16:08:13ZInhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders10.1038/s41598-017-00413-32045-2322https://doaj.org/article/9af9999edb46428491a8bdbba7942bc42017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00413-3https://doaj.org/toc/2045-2322Abstract Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia. Here we show that SGK1 directly regulates NaV1.5 channel function, and genetic inhibition of SGK1 in a zebrafish model of inherited long QT syndrome rescues the long QT phenotype. Using computer-aided drug discovery coupled with in vitro kinase assays, we identified a novel class of SGK1 inhibitors. Our lead SGK1 inhibitor (5377051) selectively inhibits SGK1 in cultured cardiomyocytes, and inhibits phosphorylation of an SGK1-specific target as well as proliferation in the prostate cancer cell line, LNCaP. Finally, 5377051 can reverse SGK1’s effects on NaV1.5 and shorten the action potential duration in induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a patient with a gain-of-function mutation in Nav 1.5 (Long QT3 syndrome). Our data suggests that SGK1 inhibitors warrant further investigation in the treatment of cardiac arrhythmias.Vassilios J. BezzeridesAifeng ZhangLing XiaoBridget SimonsonSantosh A. KhedkarShiro BabaFilomena OttavianoStacey LynchKatherine HesslerAlan C. RigbyDavid MilanSaumya DasAnthony RosenzweigNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Vassilios J. Bezzerides
Aifeng Zhang
Ling Xiao
Bridget Simonson
Santosh A. Khedkar
Shiro Baba
Filomena Ottaviano
Stacey Lynch
Katherine Hessler
Alan C. Rigby
David Milan
Saumya Das
Anthony Rosenzweig
Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders
description Abstract Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia. Here we show that SGK1 directly regulates NaV1.5 channel function, and genetic inhibition of SGK1 in a zebrafish model of inherited long QT syndrome rescues the long QT phenotype. Using computer-aided drug discovery coupled with in vitro kinase assays, we identified a novel class of SGK1 inhibitors. Our lead SGK1 inhibitor (5377051) selectively inhibits SGK1 in cultured cardiomyocytes, and inhibits phosphorylation of an SGK1-specific target as well as proliferation in the prostate cancer cell line, LNCaP. Finally, 5377051 can reverse SGK1’s effects on NaV1.5 and shorten the action potential duration in induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a patient with a gain-of-function mutation in Nav 1.5 (Long QT3 syndrome). Our data suggests that SGK1 inhibitors warrant further investigation in the treatment of cardiac arrhythmias.
format article
author Vassilios J. Bezzerides
Aifeng Zhang
Ling Xiao
Bridget Simonson
Santosh A. Khedkar
Shiro Baba
Filomena Ottaviano
Stacey Lynch
Katherine Hessler
Alan C. Rigby
David Milan
Saumya Das
Anthony Rosenzweig
author_facet Vassilios J. Bezzerides
Aifeng Zhang
Ling Xiao
Bridget Simonson
Santosh A. Khedkar
Shiro Baba
Filomena Ottaviano
Stacey Lynch
Katherine Hessler
Alan C. Rigby
David Milan
Saumya Das
Anthony Rosenzweig
author_sort Vassilios J. Bezzerides
title Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders
title_short Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders
title_full Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders
title_fullStr Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders
title_full_unstemmed Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders
title_sort inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/9af9999edb46428491a8bdbba7942bc4
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