Abstract
In recent years, Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions, including cardiac hypertrophy and uremic cardiomyopathy. Cardiotonic steroids (CTS), specific ligands of Na/K-ATPase, regulate its enzymatic activity (at higher concentrations) and signaling function (at lower concentrations without significantly affecting its enzymatic activity) and increase reactive oxygen species (ROS) generation. On the other hand, an increase in ROS alone also regulates the Na/K-ATPase enzymatic activity and signaling function. We termed this phenomenon the Na/K-ATPase-mediated oxidant-amplification loop, in which oxidative stress regulates both the Na/K-ATPase activity and signaling. Most recently, we also demonstrated that this amplification loop is involved in the development of uremic cardiomyopathy. This review aims to evaluate the redox-sensitive Na/K-ATPase-mediated oxidant amplification loop and uremic cardiomyopathy.
Highlights
For 200 years, digitalis-like drugs have been used to treat heart failure. This is based on the facts that digitalis-like drugs cause an inotropic effect by coupling the partial inhibition of the Na/K-ATPase ion-exchange activity with Na+/Ca2+ exchanger (NCX) to increase cardiac contractility
The ligands of Na/K-ATPase, cardiotonic steroids (CTSs, known as endogenous digitalis-like substances which are the base of digitalis-like drugs) have been classified as a new class of hormones, making Na/K-ATPase a potential therapeutic target [1,2,3,4]
In renal proximal tubule LLC-PK1 cells, Na/K-ATPase is involved in the glucose-oxidase-stimulated activation of the c-Src/ERK1/2 pathway [21,51], and a basal reactive oxygen species (ROS) level is required to initiate the ouabain-stimulated Na/K-ATPase signaling and protein carbonylation of two amino acid residues in the actuator domain of the Na/K-ATPase α1 subunit [21,22]
Summary
For 200 years, digitalis-like drugs have been used to treat heart failure. This is based on the facts that digitalis-like drugs cause an inotropic effect by coupling the partial inhibition of the Na/K-ATPase ion-exchange activity (increases intracellular sodium concentration, [Na+]i) with Na+/Ca2+ exchanger (NCX) (increases intracellular calcium concentration, [Ca2+]i) to increase cardiac contractility. It was demonstrated that digitalis-like drugs cause intracellular ionic changes and stimulate transcriptional upregulation of several marker genes including Na/K-ATPase itself, as well as cardiac hypertrophy and cardiac fibrosis through increased cell growth and protein synthesis.
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