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Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK/GSK-3β pathway independent of PI3K/Akt.
Toxicol Appl Pharmacol. 2015 Nov 01; 288(3):349-58.TA

Abstract

Preconditioning against myocardial ischemia-reperfusion (I/R) injury can be suppressed in some pathological conditions. This study was designed to investigate whether morphine preconditioning (MPC) exerts cardioprotection in doxorubicin (DOX)-induced heart failure in rats and the mechanisms involved. Phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt), extracellular signal-regulated kinase (ERK) and glycogen synthase kinase (GSK)-3β pathways were examined. Normal and DOX-induced failing rat hearts were subjected to I/R injury using a Langendorff perfusion system with or without MPC or ischemic preconditioning (IPC). The PI3K inhibitor (wortmannin) or ERK inhibitor (PD98059) was infused before MPC. In normal hearts, both MPC and IPC significantly reduced infarct size and the rise in lactate dehydrogenase (LDH) level caused by I/R injury. Pretreatment with wortmannin or PD98059 abrogated the protective effects of MPC and suppressed the phosphorylation of Akt, ERK and GSK-3β. In failing rat hearts, however, MPC retained its cardioprotection while IPC did not. This protective effect was abolished by PD98059 but not wortmannin. MPC increased the level of p-ERK rather than p-Akt. The phosphorylation of GSK-3β induced by MPC was reversed by PD98059 only. IPC did not elevate the expression of p-ERK, p-Akt and p-GSK-3β in failing rat hearts. We conclude that MPC is cardioprotective in rats with DOX-induced heart failure while IPC is not. The effect of MPC appears to be mediated via the ERK/GSK-3β pathway independent of PI3K/Akt.

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Authors+Show Affiliations

Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.

Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.

Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.

Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.

Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.

Department of Ultrasound, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.

Department of Anesthesiology, University of Hong Kong, Hong Kong.

Department of Anesthesiology, University of Hong Kong, Hong Kong.

Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China. Electronic address: zhangye_hassan@aliyun.com.

MeSH

AnimalsCardiotonic AgentsDoxorubicinExtracellular Signal-Regulated MAP KinasesGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHeartIschemic Preconditioning, MyocardialMaleMorphineMyocardial Reperfusion InjuryPhosphatidylinositol 3-KinasesPhosphorylationProto-Oncogene Proteins c-aktRatsRats, Sprague-DawleySignal Transduction

Pub Type(s)

Journal Article

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

Language

eng

PubMed ID

26296503

Citation

He, Shu-Fang, et al. "Morphine Preconditioning Confers Cardioprotection in Doxorubicin-induced Failing Rat Hearts Via ERK/GSK-3β Pathway Independent of PI3K/Akt." Toxicology and Applied Pharmacology, vol. 288, no. 3, 2015, pp. 349-58.

He SF, Jin SY, Wu H, et al. Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK/GSK-3β pathway independent of PI3K/Akt. Toxicol Appl Pharmacol. 2015;288(3):349-58.

He, S. F., Jin, S. Y., Wu, H., Wang, B., Wu, Y. X., Zhang, S. J., Irwin, M. G., Wong, T. M., & Zhang, Y. (2015). Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK/GSK-3β pathway independent of PI3K/Akt. Toxicology and Applied Pharmacology, 288(3), 349-58. https://doi.org/10.1016/j.taap.2015.08.007

He SF, et al. Morphine Preconditioning Confers Cardioprotection in Doxorubicin-induced Failing Rat Hearts Via ERK/GSK-3β Pathway Independent of PI3K/Akt. Toxicol Appl Pharmacol. 2015 Nov 1;288(3):349-58. PubMed PMID: 26296503.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK/GSK-3β pathway independent of PI3K/Akt. AU - He,Shu-Fang, AU - Jin,Shi-Yun, AU - Wu,Hao, AU - Wang,Bin, AU - Wu,Yun-Xiang, AU - Zhang,Shu-Jie, AU - Irwin,Michael G, AU - Wong,Tak-Ming, AU - Zhang,Ye, Y1 - 2015/08/18/ PY - 2015/06/11/received PY - 2015/08/11/revised PY - 2015/08/13/accepted PY - 2015/8/23/entrez PY - 2015/8/25/pubmed PY - 2016/1/20/medline KW - Cardioprotection KW - Doxorubicin KW - Heart failure KW - Ischemia–reperfusion injury KW - Morphine preconditioning KW - Signal pathways SP - 349 EP - 58 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 288 IS - 3 N2 - Preconditioning against myocardial ischemia-reperfusion (I/R) injury can be suppressed in some pathological conditions. This study was designed to investigate whether morphine preconditioning (MPC) exerts cardioprotection in doxorubicin (DOX)-induced heart failure in rats and the mechanisms involved. Phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt), extracellular signal-regulated kinase (ERK) and glycogen synthase kinase (GSK)-3β pathways were examined. Normal and DOX-induced failing rat hearts were subjected to I/R injury using a Langendorff perfusion system with or without MPC or ischemic preconditioning (IPC). The PI3K inhibitor (wortmannin) or ERK inhibitor (PD98059) was infused before MPC. In normal hearts, both MPC and IPC significantly reduced infarct size and the rise in lactate dehydrogenase (LDH) level caused by I/R injury. Pretreatment with wortmannin or PD98059 abrogated the protective effects of MPC and suppressed the phosphorylation of Akt, ERK and GSK-3β. In failing rat hearts, however, MPC retained its cardioprotection while IPC did not. This protective effect was abolished by PD98059 but not wortmannin. MPC increased the level of p-ERK rather than p-Akt. The phosphorylation of GSK-3β induced by MPC was reversed by PD98059 only. IPC did not elevate the expression of p-ERK, p-Akt and p-GSK-3β in failing rat hearts. We conclude that MPC is cardioprotective in rats with DOX-induced heart failure while IPC is not. The effect of MPC appears to be mediated via the ERK/GSK-3β pathway independent of PI3K/Akt. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/26296503/Morphine_preconditioning_confers_cardioprotection_in_doxorubicin_induced_failing_rat_hearts_via_ERK/GSK_3β_pathway_independent_of_PI3K/Akt_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(15)30059-4 DB - PRIME DP - Unbound Medicine ER -