title: Apelin-13 protects the heart against ischemia-reperfusion injury through the RISK-GSK-3β-mPTP pathway.
abstract: BACKGROUND
  Apelin plays an important role in the protection against myocardial ischemia-reperfusion (I/R) injury, while the mechanism still remains unclear. In the current study, we aimed to evaluate the protective effect of apelin-13, and the main mechanism.
  
  
  METHODS
  The in vivo I/R injury model (Sprague-Dawley rat) was established, then infarct size, expression levels of phospho-protein kinase B (p-Akt), phospho-extracellular signal-regulated kinase (p-ERK) and phospho-glycogen synthase kinase-3β (p-GSK-3β) were measured. The fluorescence intensity of tetramethylrhodamine ethyl ester perchlorate (TMRE) of the isolated myocardial cells was determined to evaluate the opening of the mitochondrial permeability transition pore (mPTP) caused by oxidant stress and hypoxia/reoxygenation.
  
  
  RESULTS
  For the established I/R injury model, apelin-13 and SB216763 (GSK-3β inhibitor) significantly reduced the infarct size (p < 0.05), which could be abolished by LY294002 (PI3K inhibitor), PD98059 (MEK inhibitor) and atractyloside (mPTP accelerator). The enhanced expression levels of p-Akt, p-ERK and p-GSK-3β caused by apelin-13 (p < 0.05) could be counteracted by LY294002 and PD98059. The reduced fluorescence intensity of TMRE in the H2O2/apelin-13 and H2O2/SB216763 treated groups was significantly lower (p < 0.05), indicating that apelin-13 and SB216763 could reduce the decline in mitochondrial membrane potential caused by oxidant stress, and the fluorescence intensity in the hypoxia/reoxygenation + apelin-13 group was significantly lower (p < 0.05), which suggested that apelin-13 could inhibit the mitochondrial membrane potential changes induced by hypoxia/reoxygenation.
  
  
  CONCLUSIONS
  The protective mechanism of apelin-13 might be that inactivation of GSK-3β could inhibit the opening of mPTP by activating PI3K/Akt and ERK1/2 involved in the reperfusion injury salvage kinase (RISK) pathway.
authors.affiliation: Department of Cardiology, Fengxian Central Hospital, Shanghai, China.
authors.forename: Shuansuo
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Medical Graduate, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Cardiology, Fengxian Central Hospital, Shanghai, China.
authors.forename: Guanghao
authors.initials: G
authors.lastname: Ge
authors.affiliation: Department of Cardiology, Fengxian Central Hospital, Shanghai, China.
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Fengxian Central Hospital, Shanghai, China.
authors.forename: Zengyong
authors.initials: Z
authors.lastname: Qiao
authors.affiliation: Department of Cardiology, Fengxian Central Hospital, Shanghai, China.
authors.forename: Huajin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai, China.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Fang
keywords: apelin-13; glycogen synthase kinase-3β; mitochondrial permeability transition pore; myocardial ischemia-reperfusion injury; reperfusion injury salvage kinase