Na+/H+ Exchanger 1, a Potential Therapeutic Drug Target for Cardiac Hypertrophy and Heart Failure

Figures

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  Figure 1. Schematic diagram of NHE1 topological structure. Both the N- and C- termini are located in the cytoplasm. The numbers indicate predicted transmembrane domains. Some representative amino acids are pointed out. The C-terminal hydrophilic cytoplasmic structural domain contains binding sites for a variety of proteins, including calmodulin (CaM), calcineurin (CaN), calcineurin homologous protein (CHP), and esrin/radixin/moesin (ERM), as well as cytoplasmic structural domains involved in phosphorylation and activity regulation.

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  Figure 2. Diagrammatic representation of the main intracellular signaling pathways of NHE1 regulating cardiac hypertrophy. The activation of NHE1 by Gq protein-dependent phospholipase C (PLC) and subsequent Na+ overload is likely to be a crucial promotor of cardiac hypertrophy induced by various stimuli such as endothelin 1 (ET-1), norepinephrine (NE), and angiotensin II (Ang II) acting on their respective receptors. Increases in reactive oxygen species (ROS) production caused by cardiac ischemia may be involved in the activation of the ERK1/2-p90RSK pathway and therefore interact with the phosphorylation of serine 703. Ca2+/CaM activates NHE1 through direct interaction. NHE1 activation contributes to the increases of pHi and [Na+]i. Increased [Na+]i leads to sustained [Ca2+]i elevation by acceleration of Ca2+ influx through the Na+/Ca2+ exchanger (NCX). Increased [Ca2+]i activates two Ca2+-dependent hypertrophic signaling molecules, Ca2+/CaM-dependent kinase II (CaMKII) and calcineurin (CaN). Activated CaMKII mediates the phosphorylation of histone deacetylase (HDAC), relieving or derepressing myocyte enhancer factor 2 (MEF2), whereas CaN dephosphorylates the nuclear factor of activated T…