Original Paper

JAK/STAT and PI3K/AKT Pathways Form a Mutual Transactivation Loop and Afford Resistance to Oxidative Stress-Induced Apoptosis in Cardiomyocytes
Yanjie Lu^1,2,*, Jin Zhou^1,3,*, Chaoqian Xu¹, Huixian Lin^2,4,5, Jiening Xiao^2,4,5, Zhiguo Wang^2,4,5, Baofeng Yang<sup>1,2

1</sup>Department of Pharmacology (State-Province key lab of China), Harbin Medical University,
²Institute of Cardiovascular Research, Harbin Medical University,
³Department of Internal Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin,
⁴Research Center, Montreal Heart Institute, Montreal,
⁵Department of Medicine, University of Montreal,
^*Authors with equal contributions to this study

Address of Corresponding Author

Cell Physiol Biochem 2008;21:305-314 (DOI: 10.1159/000129389)

  Key Words

• Apoptosis
• PI3K/AKT
• NF-B
• JAK2/STAT3
• Cardiomyocytes
• Signaling pathway

  Abstract

Cardiac tissues contain cells susceptible to and cells resistant to apoptosis, and this difference is important for normal morphogenesis during development and for abnormal loss of cells during pathogenesis such as myocardial infarction and heart failure. While efforts have been made to understand the cellular and intercellular events of apoptotic cells, the signaling mechanisms in cells surviving from apoptotic injuries have been overlooked. Understanding signal transduction processes in cells with apoptosis resistance is of crucial importance to develop better strategies of preserving post-mitotic cells. To this end, we performed studies in neonatal rat ventricular myocytes using oxidative stress (H₂O₂) as an apoptotic inducer. We identified a population of cells bearing higher resistance to apoptosis and found that the cells that survived from apoptotic insults had markedly higher levels of AKT and STAT3. Inhibition of AKT activity by a dominant negative AKT construct or by a PI3K inhibitor reduced active NF-B and STAT3 expression without significantly altering the activity of the latter. Activation of AKT by a constitutively activated AKT construct caused the opposite effects. Direct activation of NF-B also enhanced STAT3 expression, an effect abrogated by NF-B inhibitor. On the other hand, knockdown of STAT3 by siRNA or inhibition of STAT3 activity by decoy oligodeoxynucleotides or by JAK2 inhibitor diminished AKT expression. In conclusion, cardiomyocytes possess an apoptosis-resistant property as a cytoprotection mechanism which is likely conferred by mutual transactivation between AKT/NF-B and JAK2/STAT3, a novel crosstalk between the two signaling pathways within the networking governing the cell fate.

Copyright © 2008 S. Karger AG, Basel

  Author Contacts

Zhiguo Wang, Research Center, Montreal Heart Institute
5000 Belanger East Montreal, PQ H1T 1C8 (Canada)
Tel. +1 514 376-3330, Fax +1 514 376-4452, E-Mail wz.email@gmail.com
Baofeng Yang, Harbin Medical University, Heilongjiang 150086, P. R. (China)
Tel. +86 451 8667-9473, E-Mail yangbf@ems.hrbmu.edu.cn

  Article Information

Accepted: January 03, 2008
Published online: April 23, 2008
Number of Print Pages : 10