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Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na⁺ current, contractility, and Ca²⁺ release in murine hearts

Zhabyeyev, P; McLean, B; Chen, X; Vanhaesebroeck, B; Oudit, GY; (2019) Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na⁺ current, contractility, and Ca²⁺ release in murine hearts. Journal of Molecular and Cellular Cardiology , 132 pp. 98-109. 10.1016/j.yjmcc.2019.05.008.

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Abstract

BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) is a proto-oncogene with high activity in the heart. BYL719 (BYL) is a PI3Kα-selective small molecule inhibitor and a prospective drug for advanced solid tumors. We investigated whether acute pharmacological inhibition of PI3Kα has pro-arrhythmic effects. METHODS & RESULTS: In isolated wild-type (WT) cardiomyocytes, pharmacological inhibition of PI3Kα (BYL719) increased contractility by 28%, Ca²⁺ release by 20%, and prolonged action potential (AP) repolarization by 10–15%. These effects of BYL719 were abolished by inhibition of reverse-mode Na+/Ca²⁺ exchanger (NCX) (KB-R7943) or by inhibition of late Na⁺ current (I_{Na-L} (ranolazine). BYL719 had no effect on PI3Kα-deficient cardiomyocytes, suggesting BYL719 effects were PI3Kα-dependent and mediated via NCX and I_{Na-L·} I_{Na-L} was suppressed by activation of PI3Kα, application of exogenous intracellular PIP3, or ranolazine. Investigation of AP and Ca²⁺ release in whole heart preparations using epicardial optical mapping showed that inhibition of PI3Kα similarly led to prolongation of AP and enhancement of Ca²⁺ release. In hearts of PI3Kα-deficient mice, β-adrenergic stimulation in the presence of high Ca²⁺ oncentrations and 12-Hz burst pacing led to delayed afterdepolarizations and ventricular fibrillation. In vivo, administration of BYL719 prolonged QT interval [QT_{cF} (Fridericia) increased by 15%] in WT, but not in PI3Kα-deficient mice. CONCLUSIONS: Pharmacological inhibition of PI3Kα is arrhythmogenic due to activation of I_{Na-L} leading to increased sarcoplasmic reticulum Ca2+ load and prolonged QT interval. Therefore, monitoring of cardiac electrical activity in patients receiving PI3K inhibitors may provide further insights into the arrhythmogenic potential of PI3Ka inhibition.

Type: Article
Title: Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na⁺ current, contractility, and Ca²⁺ release in murine hearts
Location: England
DOI: 10.1016/j.yjmcc.2019.05.008
Publisher version: https://doi.org/10.1016/j.yjmcc.2019.05.008
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Adrenergic stimulation, Afterdepolarization, Arrhythmias, Long QT, PI3Kα
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/10075161
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