title: Low-concentration of perifosine surprisingly protects cardiomyocytes from oxygen glucose deprivation.
abstract: Here we found that low-concentration of perifosine, an Akt inhibitor, surprisingly protected cardiomyocytes from oxygen glucose deprivation (OGD)/re-oxygenation. In H9c2 cardiomyocytes, non-cytotoxic perifosine (0.1-0.5 μM) suppressed OGD/re-oxygenation-induced reactive oxygen species (ROS) production, p53 mitochondrial translocation and cyclophilin D complexation, as well as mitochondrial membrane potential (MMP) reduction. Molecularly, perifosine activated AMP-activated kinase (AMPK) signaling to increase intracellular NADPH (nicotinamide adenine dinucleotide phosphate) content in H9c2 cells. On the other hand, AMPK inhibition by AMPKα1 shRNA-knockdown in H9c2 cells significantly reduced perifosine-induced NADPH production, and alleviated perifosine-mediated anti-oxidant and cytoprotective activities against OGD/re-oxygenation. In primary murine cardiomyocytes, perifosine similarly activated AMPK signaling, and offered significant protection against OGD/re-oxygenation, which was largely attenuated with siRNA knockdown of AMPKα1. We demonstrate an unexpected function of perifosine (low-concentration) in protecting cardiomyocytes from OGD/re-oxygenation.
authors.affiliation: Department of Cardiology, Drum Tower Clinical Medical Hospital, Nanjing Medical University, Nanjing, China; Department of Cardiology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Koulong
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Huihe
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Yefei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Drum Tower Clinical Medical Hospital, Nanjing Medical University, Nanjing, China. Electronic address: drxuibaonanjing8@sina.com.
authors.forename: Biao
authors.initials: B
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000008:administration & dosage; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051381:Rats
chemical_list: D002316:Cardiotonic Agents; D010767:Phosphorylcholine; C105905:perifosine; D005947:Glucose
keywords: AMPK signaling; Cardiomyocytes; NADPH; Oxygen glucose deprivation (OGD)/re-oxygenation; Perifosine