title: Reduction of Na/K-ATPase potentiates marinobufagenin-induced cardiac dysfunction and myocyte apoptosis.
abstract: Decreases in cardiac Na/K-ATPase have been documented in patients with heart failure. Reduction of Na/K-ATPase α1 also contributes to the deficiency in cardiac contractility in animal models. Our previous studies demonstrate that reduction of cellular Na/K-ATPase causes cell growth inhibition and cell death in renal proximal tubule cells. To test whether reduction of Na/K-ATPase in combination with increased cardiotonic steroids causes cardiac myocyte death and cardiac dysfunction, we examined heart function in Na/K-ATPase α1 heterozygote knock-out mice (α1(+/-)) in comparison to wild type (WT) littermates after infusion of marinobufagenin (MBG). Adult cardiac myocytes were also isolated from both WT and α1(+/-) mice for in vitro experiments. The results demonstrated that MBG infusion increased myocyte apoptosis and induced significant left ventricle dilation in α1(+/-) mice but not in their WT littermates. Mechanistically, it was found that in WT myocytes MBG activated the Src/Akt/mTOR signaling pathway, which further increased phosphorylation of ribosome S6 kinase (S6K) and BAD (Bcl-2-associated death promoter) and protected cells from apoptosis. In α1(+/-) myocytes, the basal level of phospho-BAD is higher compared with WT myocytes, but MBG failed to induce further activation of the mTOR pathway. Reduction of Na/K-ATPase also caused the activation of caspase 9 but not caspase 8 in these cells. Using cultures of neonatal cardiac myocytes, we demonstrated that inhibition of the mTOR pathway by rapamycin also enabled MBG to activate caspase 9 and induce myocyte apoptosis.
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo, Toledo, Ohio 43614, USA.
authors.forename: Changxuan
authors.initials: C
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Yoann
authors.initials: Y
authors.lastname: Sottejeau
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Li
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
authors.forename: Deepak
authors.initials: D
authors.lastname: Malhotra
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cooper
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Shapiro
authors.forename: Zi-jian
authors.initials: ZJ
authors.lastname: Xie
authors.forename: Jiang
authors.initials: J
authors.lastname: Tian
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002018:Bufanolides / Q000009:adverse effects* / Q000494:pharmacology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D002018:Bufanolides; D004791:Enzyme Inhibitors; D009124:Muscle Proteins; C093896:marinobufagenin; C546843:mTOR protein, mouse; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C505526:Casp8 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D000254:Sodium-Potassium-Exchanging ATPase; D020123:Sirolimus