The Na⁺/Ca²⁺ exchanger: A possible link between oxidative stress and endogenous ouabain in hypertension

Abstract

Oxidative stress-induced hypertension involves a number of membrane transport proteins that play a critical role in maintaining the cytosolic homeostasis of Na⁺ and Ca²⁺. These transport proteins include Na⁺/K⁺-ATPase, the Na⁺/H⁺ exchanger, Na channels, and the Na⁺/Ca²⁺ exchanger. The exact link between these membrane transporters is not exactly known but appears to involve their location in microdomains called PLasmERosomes, oxidative stress and circulating ouabain levels. Oxidative stress stimulates the generation of ouabain from the adrenal glands which elevates circulating endogenous ouabain levels. At concentrations above 1nM, ouabain inhibits the activity of the Na⁺/K⁺-ATPase. At 1nM or lower concentrations, the Na⁺/K⁺-ATPase acts as a transducer which induces a cascade of events that begins with phosphorylation of the epidermal growth factor receptor (EGFR) by Src and activation of Ras, Raf, mitogen activated protein kinase kinase (MEK), mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase1/2 (ERK1/2), and p90 ribosomal S6 kinase (p90RSK). p90RSK activates the Na⁺/H⁺ exchanger through phosphorylation. Ouabain-mediated inhibition and activation of the Na⁺/K⁺-ATPase and Na⁺/H⁺ exchanger, respectively, leads to elevation of Na⁺ in the PLasmERosome which stimulates the Na⁺/Ca²⁺ exchanger to extrude Na⁺ in exchange for Ca²⁺. This elevates Ca²⁺ in the PLasmERosome which stimulates junctional ER to release Ca²⁺. Ca²⁺ influx through the Na⁺/Ca²⁺ exchanger and release from junctional ER leads to Ca²⁺ overload which can lead to a number of pathologies including increased vascular tone and hypertension.

Keywords

Oxidative stress - ouabain - sodium proton exchanger - sodium pump - sodium calcium exchanger - hypertension