Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion.
OBJECTIVE
To evaluate the significance of the JAK-STAT pathway in insulin-induced cardioprotection from reperfusion injury.


METHODS
In isolated perfused rat hearts subjected to insulin therapy (0.3 mU/ml) +/- AG490 (5 microM, JAK-STAT inhibitor), the phosphorylation state of STAT3 and Akt was determined after 15 min of reperfusion. Infarct size was measured after 120 min of reperfusion. Isolated cardiac myocytes from wild type (WT) and cardiac specific STAT3 deficient mice were treated with insulin at reoxygenation following simulated ischemia (SI, 26 h). Cell viability was measured after 120 min of reoxygenation following SI, whereas phosphorylation state of Akt was measured after 15 min of reoxygenation following SI.


RESULTS
Insulin given at reperfusion led to phosphorylation of STAT3 and Akt both of which were inhibited by AG490. AG490 also blocked the insulin-dependent decrease in infarct size, supporting a role for JAK-STAT in cardioprotection. In addition, insulin protection from SI was blocked in myocytes from the STAT3 deficient mice, or in WT mice treated with AG490. Furthermore, insulin failed to phosphorylate Akt in the STAT3 deficient cardiomyocytes.


CONCLUSIONS
Insulin-induced cardioprotection at reperfusion occurs through activation of STAT3. Inhibiting STAT3 by AG490, or STAT3 depletion in cardiac myocytes affects activation of Akt, suggesting close interaction between STAT3 and Akt in the cardioprotective signalling pathway activated by insulin treatment at reperfusion.
Fuglesteg
Britt N
BN
Dept. of Medical Physiology, Faculty of Medicine, University of Tromsø, 9037, Tromsø, Norway. brittf@fagmed.uit.no
Suleman
Naushaad
N
Tiron
Crina
C
Kanhema
Tambuzai
T
Lacerda
Lydia
L
Andreasen
Thomas V
TV
Sack
Michael N
MN
Jonassen
Anne K
AK
Mjøs
Ole D
OD
Opie
Lionel H
LH
Lecour
Sandrine
S
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007328:Insulin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen