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".

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.