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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.
Crit Care Med. 2016 Mar; 44(3):e131-45.CC

Abstract

OBJECTIVES

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.

DESIGN

Pharmacologic intervention.

SETTING

Research laboratory.

SUBJECTS

Male Sprague-Dawley rats.

INTERVENTIONS

In vivo and in vitro treatments.

MEASUREMENTS AND MAIN RESULTS

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.

CONCLUSIONS

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.

Authors+Show Affiliations

1Department of Anesthesiology, the University of Hong Kong, Hong Kong SAR, China.2Department of Anesthesiology and Critical Care, the Second Affiliated Hospital of Soochow University, Suzhou, China.3Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.4State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26468894

Citation

Qiao, Shigang, et al. "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." Critical Care Medicine, vol. 44, no. 3, 2016, pp. e131-45.
Qiao S, Mao X, Wang Y, et al. 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. Crit Care Med. 2016;44(3):e131-45.
Qiao, S., Mao, X., Wang, Y., Lei, S., Liu, Y., Wang, T., Wong, G. T., Cheung, C. W., Xia, Z., & Irwin, M. G. (2016). 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. Critical Care Medicine, 44(3), e131-45. https://doi.org/10.1097/CCM.0000000000001350
Qiao S, et al. 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. Crit Care Med. 2016;44(3):e131-45. PubMed PMID: 26468894.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Qiao,Shigang, AU - Mao,Xiaowen, AU - Wang,Yan, AU - Lei,Shaoqing, AU - Liu,Yanan, AU - Wang,Tingting, AU - Wong,Gordon T, AU - Cheung,Chi-Wai, AU - Xia,Zhengyuan, AU - Irwin,Michael G, PY - 2015/10/16/entrez PY - 2015/10/16/pubmed PY - 2016/7/13/medline SP - e131 EP - 45 JF - Critical care medicine JO - Crit Care Med VL - 44 IS - 3 N2 - OBJECTIVES: 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. DESIGN: Pharmacologic intervention. SETTING: Research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: In vivo and in vitro treatments. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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. SN - 1530-0293 UR - https://www.unboundmedicine.com/medline/citation/26468894/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_ L2 - https://dx.doi.org/10.1097/CCM.0000000000001350 DB - PRIME DP - Unbound Medicine ER -