The Remaining Conundrum of the Role of the Na+/H+ Exchanger Isoform 1 (NHE1) in Cardiac Physiology and Pathology: Can It Be Rectified?

Abstract

The mammalian Na + /H + exchanger (NHE) is a family of ubiquitous membrane proteins present in humans. Isoform one (NHE1) is present on the plasma membrane and regulates intracellular pH by removal of one intracellular proton in exchange for one extracellular sodium thus functioning as an electroneutral process. Human NHE1 has a 500 amino acid membrane domain plus a C-terminal 315 amino acid, regulatory cytosolic tail. It is regulated through a cytosolic regulatory C-terminal tail which is subject to phosphorylation and is modulated by proteins and lipids. Substantial evidence has implicated NHE1 activity in both myocardial ischemia and reperfusion damage and myocardial remodeling resulting in heart failure. Experimental data show excellent cardioprotection with NHE1 inhibitors although results from clinical results have been mixed. In cardiac surgery patients receiving the NHE1 inhibitor cariporide, subgroups showed beneficial effects of treatment. However, in one trial this was associated with a significantly increased incidence of ischemic strokes. This likely reflected both inappropriate dosing regimens as well as overly high drug doses. We suggest that further progress towards NHE1 inhibition as a treatment for cardiovascular disease is warranted through the development of novel compounds to inhibit NHE1 that are structurally different than those previously used in compromised clinical trials. Some novel pyrazinoyl guanidine inhibitors of NHE1 are already in development and the recent elucidation of the three-dimensional structure of the NHE1 protein and identity of the inhibitor binding site may facilitate development. An alternative approach may also be to control the endogenous regulation of activity of NHE1, which is activated in disease.

(Myocardium Remodelling: From Adaptation Mechanisms to Heart Failure Development)

“…Signalizace obou cest vedou ke vzestupu kalcia v buňce, rozvoji hypertrofi e a vzniku srdečního selhání. 25…”

“…6 Inhibitory aldosteronového receptoru (spironolakton) u pacientů se srdečním selháním signifi kantně snižují mortalitu a morbiditu. 25,26 In vitro bylo prokázáno, že látky jako angiotenzin nebo noradrenalin jsou schopny samy o sobě vyvolat proces hypertrofi e. 2 K hypertrofi i vyvolané katecholaminy dochází při dlouhodobé stimulaci  1 -adrenergních receptorů. Ta způsobuje receptorovou desenzitizaci -arrestinu a zvýšení exprese výměnného proteinu 1 přímo aktivovaného cAMP ( exchange protein directly activated by cAMP 1, EPAC1).…”

“…Navíc vzestup intracelulární koncentrace sodíku přímo způsobuje hypertrofi i signalizací proteinkinázou C a kyslíkovými radikály. 25 Výměník NHE-1 ( Na + /H + výměník 1) se vyskytuje ve všech buňkách těla. Jeho základní funkcí je stabilizace pH v buňce exfl uxem protonů a jeho zvýšená exprese byla pozorována u reperfuzního poškození a hypertrofi e myokardu.…”