Oxidative regulation of the Na(+)-K(+) pump in the cardiovascular system

Abstract

The Na(+)-K(+) pump is an essential heterodimeric membrane protein, which maintains electrochemical gradients for Na(+) and K(+) across cell membranes in all tissues. We have identified glutathionylation, a reversible posttranslational redox modification, of the Na(+)-K(+) pump's β1 subunit as a regulatory mechanism of pump activity. Oxidative inhibition of the Na(+)-K(+) pump by angiotensin II- and β1-adrenergic receptor-coupled signaling via NADPH oxidase activation demonstrates the relevance of this regulatory mechanism in cardiovascular physiology and pathophysiology. This has implications for dysregulation of intracellular Na(+) and Ca(2+) as well as increased oxidative stress in heart failure, myocardial ischemia-reperfusion, and regulation of vascular tone under conditions of elevated oxidative stress. Treatment strategies that are able to reverse this oxidative inhibition of the Na(+)-K(+) pump have the potential for cardiovascular-protective effects.

Keywords: Free radicals; Glutaredoxin; Glutathionylation; NADPH oxidase; Na(+)–K(+) pump.