title: Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK/GSK-3β pathway independent of PI3K/Akt.
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.
authors: Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
authors: Shu-Fang
authors: SF
authors: He
authors: Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
authors: Shi-Yun
authors: SY
authors: Jin
authors: Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
authors: Hao
authors: H
authors: Wu
authors: Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
authors: Bin
authors: B
authors: Wang
authors: Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
authors: Yun-Xiang
authors: YX
authors: Wu
authors: Department of Ultrasound, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
authors: Shu-Jie
authors: SJ
authors: Zhang
authors: Department of Anesthesiology, University of Hong Kong, Hong Kong.
authors: Michael G
authors: MG
authors: Irwin
authors: Department of Anesthesiology, University of Hong Kong, Hong Kong.
authors: Tak-Ming
authors: TM
authors: Wong
authors: Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China. Electronic address: zhangye_hassan@aliyun.com.
authors: Ye
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000009:adverse effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D002316:Cardiotonic Agents; D009020:Morphine; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3
keywords: Cardioprotection; Doxorubicin; Heart failure; Ischemia–reperfusion injury; Morphine preconditioning; Signal pathways