Hypoxic Stress-Dependent Regulation of Na,K-ATPase in Ischemic Heart Disease

Abstract

In cardiomyocytes, regular activity of the Na,K-ATPase (NKA) and its Na/K pump activity is essential for maintaining ion gradients, excitability, propagation of action potentials, electro-mechanical coupling, trans-membrane Na⁺ and Ca²⁺ gradients and, thus, contractility. The activity of NKA is impaired in ischemic heart disease and heart failure, which has been attributed to decreased expression of the NKA subunits. Decreased NKA activity leads to intracellular Na⁺ and Ca²⁺ overload, diastolic dysfunction and arrhythmias. One signal likely related to these events is hypoxia, where hypoxia-inducible factors (HIF) play a critical role in the adaptation of cells to low oxygen tension. HIF activity increases in ischemic heart, hypertension, heart failure and cardiac fibrosis; thus, it might contribute to the impaired function of NKA. This review will mainly focus on the regulation of NKA in ischemic heart disease in the context of stressed myocardium and the hypoxia-HIF axis and argue on possible consequences of treatment.

Keywords: HIF; Na,K-ATPase; cardiotonic steroids; cellular stress; heart failure; hypoxia; ion transporter; ischemic heart.

Figure 2

Modulation of NKA activity in an ischemic heart. Catecholamines, angiotensin II and isoproterenol stimulate relevant receptors, increase HIF, and their levels gradually increase during the progression of heart failure. Increased HIF might be involved in regulating NKA in the ischemic heart. Hypoxia, by changing the redox status of cardiomyocytes, causes posttranslational modifications of the NKA subunits, and by decreasing membrane expression of the subunits inhibits NKA. Inflammatory cytokines via PI3K/Rac1/NADPH oxidase cascade inhibits NKA. Furthermore, cardiotonic steroids inhibit NKA, leading to elevated intracellular Na⁺ and Ca²⁺ levels, which further deteriorate cardiac contraction and function.

Figure 3

Possible regulation of NKA by HIF in the hypoxic myocardium. HIF: hypoxia inducible factor; CTS: cardiotonic steroids.

Figure 1

Structure (A) and function (B) of NKA.