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

Abstract

Cardiac hypertrophy is defined as increased heart mass in response to increased hemodynamic requirements. Long-term cardiac hypertrophy, if not counteracted, will ultimately lead to heart failure. The incidence of heart failure is related to myocardial infarction, which could be salvaged by reperfusion and ultimately invites unfavorable myocardial ischemia-reperfusion injury. The Na+/H+ exchangers (NHEs) are membrane transporters that exchange one intracellular proton for one extracellular Na+. The first discovered NHE isoform, NHE1, is expressed almost ubiquitously in all tissues, especially in the myocardium. During myocardial ischemia-reperfusion, NHE1 catalyzes increased uptake of intracellular Na+, which in turn leads to Ca2+ overload and subsequently myocardial injury. Numerous preclinical research has shown that NHE1 is involved in cardiac hypertrophy and heart failure, but the exact molecular mechanisms remain elusive. The objective of this review is to demonstrate the potential role of NHE1 in cardiac hypertrophy and heart failure and investigate the underlying mechanisms.

Investigating the mechanism of action of Danhong injection and its components against myocardial ischemia-reperfusion injury

“…Regarding the protons present in cells, their numbers increased with anaerobic glycolysis during ischemia and flowed out from the cells through Na + /H + exchanger, with intracellular Na + influx. As the activity of Na + /K + -ATPase decreased, intracellular Na + accumulated, which led to a subsequent influx of Ca 2 + into the cells through the reversed Na + / Ca 2 + exchanger, thereby causing Ca 2 + overload [45][46][47] . After reperfusion, extracellular pH rapidly returned to normal, which may have led to further depletion of ATP and damage to cardiomyocytes [48][49] .…”

Influence of acidic metabolic environment on differentiation of stem cell-derived cardiomyocytes

“…NHE is a common plasma membrane glycoprotein that regulates intracellular pH by expelling an intracellular proton in exchange for an extracellular sodium ion, thereby removing excessive intracellular acid ( 13 ). Although there are nine isoforms of NHE, NHE1 is the only plasma membrane isoform in the heart ( 27 ). An assessment of the contribution of each transporter protein to removing intracellular acid indicated that NHE1 is the major transporter protein reducing intracellular acid loads in cardiomyocytes ( 28 ).…”

Inhibition of Na/H exchanger-1 in the right ventricle and lung dysfunction induced by experimental pulmonary arterial hypertension in rats

“…The Na + /H + exchange is a pleiotropic mechanism that ensures the control of pHi in most mammalian cells 39 . Of the several diseases potentially triggered by NHE dysfunction, the onset of cardiac fibrosis in Duchenne and Becker muscular dystrophy provided a bench to test RIME as an antagonist of the molecular pathways leading to PAH 13 .…”