Journal Article

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

Ling Xiao, Aifeng Zhang, Katherine Hessler, Shiro Baba, Saumya Das, Santosh Khedkar, Alan C. Rigby, Bridget Simonson, Filomena G. Ottaviano, Anthony Rosenzweig, David J. Milan, Stacey N. Lynch, Vassilios J. Bezzerides

2017

Overview

Alterations in sodium flux (I Na ) 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 Na V 1.5 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 Na V 1.5 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 Na V 1.5 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.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Portfolio
• Subject: 119/118 / 631/154 / 64/116 / 692/4019 / 82/1 / 9/74 / Animals / Arrhythmias, Cardiac / Arrhythmias, Cardiac - therapy / Cells, Cultured / Disease Models, Animal / Humanities and Social Sciences / Humans / Immediate-Early Proteins / Immediate-Early Proteins - genetics / Immediate-Early Proteins - metabolism / Medicine / multidisciplinary / Myocytes, Cardiac / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - physiology / NAV1.5 Voltage-Gated Sodium Channel / NAV1.5 Voltage-Gated Sodium Channel - metabolism / Protein Interaction Mapping / Protein Kinase Inhibitors / Protein Kinase Inhibitors - isolation & purification / Protein Kinase Inhibitors - pharmacology / Protein Serine-Threonine Kinases / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Q / R / Science / Science (multidisciplinary) / Zebrafish