title: Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning.
abstract: Acute myocardial infarction, the clinical manifestation of ischemia-reperfusion (IR) injury, is a leading cause of death worldwide. Like ischemic preconditioning (IPC) induced by brief episodes of ischemia and reperfusion, ouabain preconditioning (OPC) mediated by Na/K-ATPase signaling protects the heart against IR injury. Class I PI3K activation is required for IPC, but its role in OPC has not been investigated. While PI3K-IB is critical to IPC, studies have suggested that ouabain signaling is PI3K-IA-specific. Hence, a pharmacological approach was used to test the hypothesis that OPC and IPC rely on distinct PI3K-I isoforms. In Langendorff-perfused mouse hearts, OPC was initiated by 4 min of ouabain 10 μM and IPC was triggered by 4 cycles of 5 min ischemia and reperfusion prior to 40 min of global ischemia and 30 min of reperfusion. Without affecting PI3K-IB, ouabain doubled PI3K-IA activity and Akt phosphorylation at Ser(473). IPC and OPC significantly preserved cardiac contractile function and tissue viability as evidenced by left ventricular developed pressure and end-diastolic pressure recovery, reduced lactate dehydrogenase release, and decreased infarct size. OPC protection was blunted by the PI3K-IA inhibitor PI-103, but not by the PI3K-IB inhibitor AS-604850. In contrast, IPC-mediated protection was not affected by PI-103 but was blocked by AS-604850, suggesting that PI3K-IA activation is required for OPC while PI3K-IB activation is needed for IPC. Mechanistically, PI3K-IA activity is required for ouabain-induced Akt activation but not PKCε translocation. However, in contrast to PKCε translocation which is critical to protection, Akt activity was not required for OPC. Further studies shall reveal the identity of the downstream targets of this new PI3K IA-dependent branch of OPC. These findings may be of clinical relevance in patients at risk for myocardial infarction with underlying diseases and/or medication that could differentially affect the integrity of cardiac PI3K-IA and IB pathways.
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA; Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Marshall Institute for Interdisciplinary Research, Huntington, WV, USA.
authors.forename: Namrata D
authors.initials: ND
authors.lastname: Madan
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kalisz
authors.affiliation: Marshall Institute for Interdisciplinary Research, Huntington, WV, USA.
authors.forename: Krunal Y
authors.initials: KY
authors.lastname: Doshi
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: Saptarsi M
authors.initials: SM
authors.lastname: Haldar
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA; Marshall Institute for Interdisciplinary Research, Huntington, WV, USA. Electronic address: pierres@marshall.edu.
authors.forename: Sandrine V
authors.initials: SV
authors.lastname: Pierre
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D005663:Furans / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010042:Ouabain / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D002867:Chromones; D005663:Furans; D007527:Isoenzymes; D009025:Morpholines; D010042:Ouabain; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; C522973:PI103; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: Ischemia–reperfusion injury; Na/K-ATPase; PI3K; Preconditioning