The ability of cells to adapt to low-oxygen conditions is associated with glutathionylation of Na,K-ATPase

Abstract

The decrease in the oxygen content of tissues, which is observed in a number of pathological processes, inevitably leads to damage. One of the main causes of cell damage and death in hypoxia is the failure of the systems that maintain the ionic balance. Na,K-ATPase is the main ion-transporting protein in the plasma membrane of animal cells, and its inhibition at low concentrations of oxygen is one of the earliest and most critical events for cell viability. Scientists are currently conducting an active search for regulators of Na,K-ATPase activity. Cardiac glycosides traditionally used for this purpose induce severe side effects, which necessitates the search for alternative inhibitors of Na,K-ATPase. We have previously found that glutathionylation of the Na,K-ATPase catalytic subunit leads to a complete inhibition of the enzyme. The present study demonstrates that the substances that increase the level of glutathionylation in Na,K-ATPase, namely, ethyl glutathione (et-GSH), oxidized glutathione (GSSG), and N-acetylcysteine (NAC), enhance cell survival under low-oxygen conditions, prevent ATP depletion, and normalize the redox status of the cells. The following concentration range in which these substances have the maximum protective effect and no pronounced cytotoxic properties was determined to be as follows: 0.2–0.5 mM et-GSH, 0.2–1 mM GSSG, and 10–15 mM NAC. These results demonstrate the prospects of developing methods of protecting tissues from damage under low-oxygen conditions that are based on changes in Na,K-ATPase glutathionylation.