Faculty Collaboration Database

The JAK/STAT pathway is essential for opioid-induced cardioprotection: JAK2 as a mediator of STAT3, Akt, and GSK-3 beta. Am J Physiol Heart Circ Physiol 2006 Aug;291(2):H827-34

Date

03/07/2006

Pubmed ID

16517948

DOI

10.1152/ajpheart.00003.2006

Scopus ID

2-s2.0-33746859331 (requires institutional sign-in at Scopus site)   174 Citations

Abstract

We examined the role for the JAK/STAT signaling pathway in acute opioid-induced cardioprotection (OIC) and whether opioid-induced glycogen synthase kinase-3beta (GSK-3 beta) inhibition is mediated by the JAK/STAT pathway. Rats underwent 30 min of ischemia and either 5 min or 2 h of reperfusion, followed by tissue isolation for molecular analysis or infarct size assessment, respectively. Rats were treated with vehicle, morphine (300 microg/kg), the delta-opioid agonist fentanyl isothiocynate (FIT, 10 microg/kg), or the GSK inhibitor SB-216763 (SB21, 600 microg/kg) 10 min before ischemia. Five minutes before opioid or SB21 treatment, some rats received the putative JAK2 inhibitor AG-490 (3 mg/kg) or the putative JAK3 inhibitor ZM-449829 (3 mg/kg). H9C2 cardiomyoblast cells were also used to investigate FIT-induced signaling (1 microM) in vitro via molecular analysis. Morphine induced the phosphorylation of JAK2, yet not JAK1, in the area at risk. Morphine, FIT, and SB21 also reduced infarct size compared with vehicle (water) when administered before ischemia [43.0 +/- 2.8, 39.1 +/- 3.1, and 42.1 +/- 2.5 (*P < 0.001, respectively) vs. 58.1 +/- 1.3%, respectively]. AG-490 abrogated OIC, whereas ZM-449829 had no effect on OIC. Cardioprotection was afforded by SB21 even in the presence of AG-490. Morphine phosphorylated STAT3, Akt, and GSK-3beta, and phosphorylation was abrogated by AG-490. FIT stimulation of H9C2 cells also caused a time-dependent phosphorylation of STAT3, Akt, and GSK-3beta, and this effect was abrogated by AG-490. STAT3 phosphorylation was also dependent on phosphatidylinositol 3-kinase (PI3K) activation in both tissue and H9C2 cells. These data suggest that OIC occurs via the JAK2 regulation of PI3K pathway-dependent STAT3, Akt, and GSK-3 beta, with GSK-3 beta contributing a central role in acute OIC.

Author List

Gross ER, Hsu AK, Gross GJ

MESH terms used to index this publication - Major topics in bold

Animals
Cardiotonic Agents
Cell Line
Enzyme Inhibitors
Fentanyl
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Hemodynamics
Immunohistochemistry
Janus Kinase 2
Male
Morphine
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
Narcotics
Oncogene Protein v-akt
Phosphatidylinositol 3-Kinases
Phosphorylation
Protein-Tyrosine Kinases
Proto-Oncogene Proteins
Rats
Rats, Sprague-Dawley
STAT1 Transcription Factor
STAT3 Transcription Factor
Signal Transduction