Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development.
V, B., N, D., NP, T., YV, S., P, B., KI, T., GS, M., D, P., & L, L. (2026). Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development.. Cell biochemistry and function. https://doi.org/10.1002/cbf.70291
V B, N D, NP T, YV S, P B, KI T, et al. Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development.. Cell biochemistry and function. 2026; doi: 10.1002/cbf.70291
V B, N D, NP T, et al. Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development.[J]. Cell biochemistry and function. 2026. DOI: 10.1002/cbf.70291.
@article{v2026,
author = {Bouratzis V and Douskou N and Tzavellas NP and Simos YV and Bozidis P and Tsamis KI and Markopoulos GS and Peschos D and Lakkas L},
title = {Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development.},
journal = {Cell biochemistry and function},
year = {2026},
doi = {10.1002/cbf.70291},
note = {PMID: 42677384},
}
TY - JOUR AU - Bouratzis V AU - Douskou N AU - Tzavellas NP AU - Simos YV AU - Bozidis P AU - Tsamis KI AU - Markopoulos GS AU - Peschos D AU - Lakkas L TI - Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development. T2 - Cell biochemistry and function PY - 2026 DO - 10.1002/cbf.70291 AN - PMID:42677384 ER -
NHE-1 is a Na+/H+ exchanger that receives phosphorylation signals, binds calmodulin and responds to neurohormonal input from angiotensin II, endothelin-1, and adrenergic pathways. In cardiac myocytes, NHE-1 maintains pH homeostasis and couples to Na+/Ca2+ exchange and mitochondrial ion handling. During heart disease sustained activation drives intracellular Na+ accumulation, promoting Ca2+ overload and mitochondrial dysfunction. Oxidative stress then creates amplifying cycles that activate signaling pathways resulting to arrhythmias and fibrosis. Clinical trials failed despite preclinical promise, due to a variety of false experimental factors. SGLT2 inhibitors appear to modulate NHE-1 indirectly through metabolic reprogramming and hemodynamic effects rather than direct blockade. Current approaches use structural data to target regulatory sites and phosphorylation-dependent conformational states instead of the transport pore. Translation to patients will require biomarkers identifying pathological hyperactivity and better patient stratification methods. Here, we try to review NHE-1 structure, regulation, and physiology that may influence research on future drug development.