title: Apelin-13 protects the heart against ischemia-reperfusion injury through inhibition of ER-dependent apoptotic pathways in a time-dependent fashion.
abstract: Endoplasmic reticulum (ER) stress is activated during and contributes to ischemia-reperfusion (I/R) injury. Attenuation of ER stress-induced apoptosis protects the heart against I/R injury. Using apelin, a ligand used to activate the apelin APJ receptor, which is known to be cardioprotective, this study was designed to investigate 1) the time course of changes in I/R injury after ER stress; 2) whether apelin infusion protects the heart against I/R injury via modulation of ER stress-dependent apoptosis signaling pathways; and 3) how phosphatidylinositol 3-kinase (PI3K)/Akt, endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK), and ERK activation are involved in the protection offered by apelin treatment. The results showed that, using an in vivo rat I/R model induced by 30 min of ischemia followed by reperfusion, infarct size (IS) increased from 2 h of reperfusion (34.85 ± 2.14%) to 12 h of reperfusion (48.98 ± 3.35, P < 0.05), which was associated with an abrupt increase in ER stress-dependent apoptosis activation, as evidenced by increased CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and JNK activation (CHOP: 2.49-fold increase, caspase-12: 2.09-fold increase, and JNK: 3.38-fold increase, P < 0.05, respectively). Administration of apelin at 1 μg/kg not only completely abolished the activation of ER stress-induced apoptosis signaling pathways at 2 h of reperfusion but also significantly attenuated time-related changes at 24 h of reperfusion. Using pharmacological inhibition, we also demonstrated that PI3K/Akt, AMPK, and ERK activation were involved in the protection against I/R injury via inhibition of ER stress-dependent apoptosis activation. In contrast, although eNOS activation played a role in decreasing IS at 2 h of reperfusion, it failed to modify either IS or ER stress-induced apoptosis signaling pathways at 24 h after reperfusion.
authors.affiliation: Division of Cardiology, Shanghai Sixth Hospital, Shanghai Jiao Tong University School of Medicine, State Key Discipline Cardiology, Shanghai, People's Republic of China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Tao
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Yapeng
authors.initials: Y
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Xin
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Mingya
authors.initials: M
authors.lastname: Liu
authors.forename: Jingbo
authors.initials: J
authors.lastname: Li
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Redington
authors.forename: Meng
authors.initials: M
authors.lastname: Wei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002316:Cardiotonic Agents; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D018613:Microscopy, Confocal; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000401:mortality / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D002316:Cardiotonic Agents; D036341:Intercellular Signaling Peptides and Proteins; C495199:apelin-13 peptide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases