title: Ischemia/reperfusion-induced alterations of enzymatic and signaling functions of the rat cardiac Na+/K+-ATPase: protection by ouabain preconditioning.
abstract: Cardiac glycosides (CG) are traditionally known as positive cardiac inotropes that inhibit Na+/K+-ATPase-dependent ion transport. CG also trigger-specific signaling pathways through the cardiac Na+/K+-ATPase, with beneficial effects in ischemia/reperfusion (I/R) injury (e.g., ouabain preconditioning, known as OPC) and hypertrophy. Our current understanding of hypersensitivity to CG and subsequent toxicity in the ischemic heart is mostly based on specific I/R-induced alterations of the Na+/K+-ATPase enzymatic function and has remained incomplete. The primary goal of this study was to investigate and compare the impact of I/R on Na+/K+-ATPase enzymatic and signaling functions. Second, we assessed the impact of OPC on both functions. Langendorff-perfused rat hearts were exposed to 30 min of ischemia and 30 min of reperfusion. At the inotropic concentration of 50 μmol/L, ouabain increased ERK and Akt phosphorylation in control hearts. In I/R hearts, this concentration did not induced positive inotropy and failed to induce Akt or ERK phosphorylation. The inotropic response to dobutamine as well as insulin signaling persisted, suggesting specific alterations of Na+/K+-ATPase. Indeed, Na+/K+-ATPase protein expression was intact, but the enzyme activity was decreased by 60% and the enzymatic function of the isoform with high affinity for ouabain was abolished following I/R. Strikingly, OPC prevented all I/R-induced alterations of the receptor. Further studies are needed to reveal the respective roles of I/R-induced modulations of Na+/K+-ATPase enzymatic and signaling functions in cardiomyocyte death.
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio.
authors.forename: Aude
authors.initials: A
authors.lastname: Belliard
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio.
authors.forename: Gaurav K
authors.initials: GK
authors.lastname: Gulati
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio Marshall Institute for Interdisciplinary Research, Huntington, West Virginia.
authors.forename: Rosana
authors.initials: R
authors.lastname: Alves
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio.
authors.forename: Shannon
authors.initials: S
authors.lastname: Brewer
authors.affiliation: Marshall Institute for Interdisciplinary Research, Huntington, West Virginia.
authors.forename: Namrata
authors.initials: N
authors.lastname: Madan
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Sottejeau
authors.affiliation: Marshall Institute for Interdisciplinary Research, Huntington, West Virginia.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kalisz
authors.affiliation: Marshall Institute for Interdisciplinary Research, Huntington, West Virginia pierres@marshall.edu.
authors.forename: Sandrine V
authors.initials: SV
authors.lastname: Pierre
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism* / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010042:Ouabain / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D010042:Ouabain; D051057:Proto-Oncogene Proteins c-akt; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Akt; ERK; Na+/K+‐ATPase α1 and α2 isoforms; activity