STAT3α interacts with nuclear GSK3beta and cytoplasmic RISK pathway and stabilizes rhythm in the anoxic-reoxygenated

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Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity
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Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity

Published on: July 10, 2019

Sarah Pedretti1, Eric Raddatz

  • 1Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Switzerland. sarah.pedretti@unil.ch

Basic Research in Cardiology
|February 1, 2011
PubMed

Insights

The Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway protects developing hearts from anoxia-induced arrhythmias. Inhibition of JAK2/STAT3 worsens cardiac dysfunction during reoxygenation.

Area of Science:

  • Cardiovascular Research
  • Developmental Biology
  • Molecular Cardiology

Background:

  • The Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway is crucial for heart development and protection against ischemia-reperfusion injury in adults.
  • The role and interactions of the JAK2/STAT3 pathway in the developing heart during transient anoxia remain largely unexplored.

Purpose of the Study:

  • To investigate the involvement of the JAK2/STAT3 pathway and its interaction with other signaling cascades in the embryonic heart subjected to anoxia-reoxygenation.
  • To determine the functional consequences of JAK2/STAT3 inhibition on cardiac electrophysiological and mechanical properties during reoxygenation.

Main Methods:

  • Isolated hearts from 4-day-old chick embryos were exposed to 30 minutes of anoxia followed by 80 minutes of reoxygenation.
  • Hearts were treated with an antioxidant (MPG), a JAK2/STAT3 inhibitor (AG490), or a PI3K/Akt inhibitor (LY-294002).
  • Phosphorylation of STAT3 and Reperfusion Injury Salvage Kinase (RISK) proteins, STAT3 DNA-binding, and cardiac function were assessed.

Main Results:

  • Reoxygenation increased STAT3 phosphorylation, which was reduced by MPG and AG490 but not LY-294002.
  • STAT3 translocated to the nucleus upon reoxygenation but without DNA-binding activity.
  • AG490 inhibited reoxygenation-induced phosphorylation of Akt, ERK2, and GSK3beta, exclusively in the nucleus.
  • Inhibition of JAK2/STAT3 impaired recovery of heart rate, increased cardiac cycle length variability, and prolonged arrhythmias.

Conclusions:

  • Oxyradical-activated STAT3α in the embryonic heart translocates to the nucleus without transcriptional activity and interacts with RISK proteins.
  • The JAK2/STAT3 pathway plays a protective role against anoxia-reoxygenation-induced arrhythmias in the developing heart.
  • STAT3 signaling interacts with RISK pathways, influencing cardiac function during oxidative stress in early development.

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