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Remifentanil Preconditioning Reduces Postischemic Myocardial Infarction and Improves Left Ventricular Performance via Activation of the Janus Activated Kinase-2/Signal Transducers and Activators of Transcription-3 Signal Pathway and Subsequent Inhibition of Glycogen Synthase Kinase-3β in Rats
- Source :
- Critical care medicine. 44(3)
- Publication Year :
- 2015
-
Abstract
- Remifentanil preconditioning attenuates myocardial ischemia reperfusion injury, but the underlying mechanism is incompletely understood. The Janus activated kinase-2 (JAK2)/signal transducers and activators of transcription-3 (STAT3) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways are critical in both ischemic and pharmacologic preconditioning cardioprotection, which involve the inactivation of glycogen synthase kinase-3β. We hypothesized that remifentanil preconditioning confers cardioprotection via the JAK2/STAT3 and/or PI3K/Akt activation-mediated glycogen synthase kinase-3β inhibition.Pharmacologic intervention.Research laboratory.Male Sprague-Dawley rats.In vivo and in vitro treatments.Male Sprague-Dawley rats (n = 6 per group) were sham operated or subjected to myocardial ischemia reperfusion injury. The JAK2 inhibitor AG490 (3 mg/kg), the PI3K inhibitor wortmannin (15 μg/kg), or the glycogen synthase kinase-3β inhibitor SB216763 (600 μg/kg) were given before inducing in vivo myocardial ischemia reperfusion injury achieved by occluding coronary artery for 30 minutes followed by 120 minutes of reperfusion in the absence or presence of remifentanil preconditioning (6 μg/kg/min). Also, isolated rat hearts were Langendorff perfused and subjected to 30 minutes of global ischemia and 120 minutes of reperfusion without or with remifentanil preconditioning (100 ng/mL) in the presence or absence of AG490 and/or SB216763. Isolated rat cardiomyocytes and H9C2 cells were subjected to hypoxia/reoxygenation alone or in combination with AG490 (100 μM), wortmannin (100 nM), or SB216763 (3 μM) without or with remifentanil preconditioning (2.5 μM). Remifentanil preconditioning reduced postischemic myocardial infarction and hemodynamic dysfunction induced by myocardial ischemia reperfusion injury concomitant with increased phosphorylation of STAT3 at tyr-705 (p-STAT3) and glycogen synthase kinase-3β but not Akt. AG490 but not wortmannin cancelled remifentanil preconditioning cardioprotection, and SB216763 restored it despite the presence of AG490. In Langendorff-perfused hearts, AG490-mediated cancellation of remifentanil preconditioning cardioprotection in attenuating postischemic myocardial infarction and creatinine kinase-MB release was reverted by concomitant administration of SB216763. Remifentanil preconditioning also attenuated posthypoxic cardiomyocyte injury and increased p-STAT3 and glycogen synthase kinase-3β in isolated primary cardiomyocytes and H9C2 cells. STAT3 gene knockdown with specific synthetic RNA cancelled remifentanil preconditioning cardioprotection, whereas glycogen synthase kinase-3β gene knockdown, which per se did not affect STAT3 under hypoxia/reoxygenation condition, preserved remifentanil preconditioning cardioprotection regardless of STAT3 abrogation.Remifentanil preconditioning confers cardioprotection primarily via activation of JAK2/STAT3 signaling that can function independent of PI3K/Akt activation. Glycogen synthase kinase-3β is a critical downstream effector of remifentanil preconditioning cardioprotection.
- Subjects :
- 0301 basic medicine
Male
STAT3 Transcription Factor
Myocardial Infarction
Myocardial Reperfusion Injury
030204 cardiovascular system & hematology
Critical Care and Intensive Care Medicine
Ventricular Function, Left
Rats, Sprague-Dawley
Remifentanil
03 medical and health sciences
Glycogen Synthase Kinase 3
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Piperidines
GSK-3
Medicine
Animals
Myocytes, Cardiac
Phosphorylation
STAT3
Ischemic Preconditioning
GSK3B
Protein kinase B
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
Janus kinase 2
Glycogen Synthase Kinase 3 beta
biology
business.industry
Janus Kinase 2
Cell biology
Rats
030104 developmental biology
Anesthesia
biology.protein
Ischemic preconditioning
Signal transduction
business
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 15300293
- Volume :
- 44
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Critical care medicine
- Accession number :
- edsair.doi.dedup.....db336796236450f2458a5e33281581dc