title: Redox-dependent regulation of the Na⁺-K⁺ pump: new twists to an old target for treatment of heart failure.
abstract: By the time it was appreciated that the positive inotropic effect of cardiac glycosides is due to inhibition of the membrane Na(+)-K(+) pump, glycosides had been used for treatment of heart failure on an empiric basis for ~200 years. The subsequent documentation of their lack of clinical efficacy and possible harmful effect largely coincided with the discovery that a raised Na(+) concentration in cardiac myocytes plays an important role in the electromechanical phenotype of heart failure syndromes. Consistent with this, efficacious pharmacological treatments for heart failure have been found to stimulate the Na(+)-K(+) pump, effectively the only export route for intracellular Na(+) in the heart failure. A paradigm has emerged that implicates pump inhibition in the raised Na(+) levels in heart failure. It invokes protein kinase-dependent activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and glutathionylation, a reversible oxidative modification, of the Na(+)-K(+) pump molecular complex that inhibits its activity. Since treatments of proven efficacy reverse the oxidative Na(+)-K(+) pump inhibition, the pump retains its status as a key pharmacological target in heart failure. Its role as a target is well integrated with the paradigms of neurohormonal abnormalities, raised myocardial oxidative stress and energy deficiency implicated in the pathophysiology of the failing heart. We propose that targeting oxidative inhibition of the pump is useful for the exploration of future treatment strategies. This article is part of a Special Issue entitled "Na(+)Regulation in Cardiac Myocytes".
authors.affiliation: North Shore Heart Research Group, Kolling Medical Research Institute, University of Sydney, Australia.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Liu
authors.forename: Natasha A S
authors.initials: NA
authors.lastname: Fry
authors.forename: Elisha J
authors.initials: EJ
authors.lastname: Hamilton
authors.forename: Karin K M
authors.initials: KK
authors.lastname: Chia
authors.forename: Alvaro
authors.initials: A
authors.lastname: Garcia
authors.forename: Keyvan
authors.initials: K
authors.lastname: Karimi Galougahi
authors.forename: Gemma A
authors.initials: GA
authors.lastname: Figtree
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Clarke
authors.forename: Henning
authors.initials: H
authors.lastname: Bundgaard
authors.forename: Helge H
authors.initials: HH
authors.lastname: Rasmussen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D008565:Membrane Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C069141:phospholemman; D011494:Protein Kinases; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ACE; AR; Ang II; GSH; Grx1; Heart failure; I(p); NADPH oxidase; NO; Na(+)–K(+) pump; ONOO(−); PKA; PKC; PKG; PP2A; Redox regulation; [Na(+)](i); adrenergic receptor; angiotensin II; angiotensin converting enzyme; cAMP; cyclic adenosine monophosphate, πGST, π isoform of glutathione S-transferase; electrogenic Na(+)–K(+) pump current; glutaredoxin 1; glutathione; intracellular Na(+) concentration; nicotinamide adenine dinucleotide phosphate-oxidase; nitric oxide; peroxynitrite; protein kinase A; protein kinase C; protein kinase G; protein phosphatase 2A; sGC; soluble guanylyl cyclase