Augmentation of Ouabain-Induced Increase in Heart Muscle Contractility by Akt Inhibitor MK-2206

Nahum Buzaglo, Mordechai Golomb, Haim Rosen, Ronen Beeri, Hagit Cohen Ben Ami, Fattal Langane, Sandrine Pierre, David Lichtstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Cardiac steroids (CSs), such as ouabain and digoxin, increase the force of contraction of heart muscle and are used for the treatment of congestive heart failure (CHF). However, their small therapeutic window limits their use. It is well established that Na + , K + -ATPase inhibition mediates CS-induced increase in heart contractility. Recently, the involvement of intracellular signal transduction was implicated in this effect. The aim of the present study was to test the hypothesis that combined treatment with ouabain and Akt inhibitor (MK-2206) augments ouabain-induced inotropy in mammalian models. We demonstrate that the combined treatment led to an ouabain-induced increase in contractility at concentrations at which ouabain alone was ineffective. This was shown in 3 experimental systems: neonatal primary rat cardiomyocytes, a Langendorff preparation, and an in vivo myocardial infarction induced by left anterior descending coronary artery (LAD) ligation. Furthermore, cell viability experiments revealed that this treatment protected primary cardiomyocytes from MK-2206 toxicity and in vivo reduced the size of scar tissue 10 days post-LAD ligation. We propose that Akt activity imposes a constant inhibitory force on muscle contraction, which is attenuated by low concentrations of MK-2206, resulting in potentiation of the ouabain effect. This demonstration of the increase in the CS effect advocates the development of the combined treatment in CHF.

Original languageAmerican English
Pages (from-to)78-89
Number of pages12
JournalJournal of Cardiovascular Pharmacology and Therapeutics
Volume24
Issue number1
DOIs
StatePublished - 1 Jan 2019

Bibliographical note

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study has been supported in part by the Sam Lazarus Fellowship, The Hebrew University, to N.B.

Publisher Copyright:
© The Author(s) 2018.

Keywords

  • Akt inhibitor
  • cardiac pharmacology
  • cardiac steroids
  • experimental cardiology

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