The Na+/H+ Exchanger: A Target for Cardiac Therapeutic Intervention

Abstract

The Na(+)/H(+) exchanger (NHE) is a ubiquitous protein present in mammalian cells. In higher eukaryotes this integral membrane protein removes one intracellular H(+) for one extracellular Na(+) protecting cells from intracellular acidification. NHE is of essential importance in the myocardium. It prevents intracellular acidosis that inhibits contractility. NHE also plays a key role in damage to the mammalian myocardium that occurs during ischemia and reperfusion and is involved in hypertrophy of the myocardium. NHE is composed of a membrane bound domain of approximately 500 amino acids plus a hydrophilic regulatory cytoplasmic domain of approximately 315 amino acids. The NHE1 isoform is the only significant plasma membrane isoform present in the myocardium. The activity of NHE1 is elevated in animal models of myocardial infarcts and in left ventricular hypertrophy. During ischemia and reperfusion of the myocardium, NHE activity catalyzes increased uptake of intracellular sodium. This in turn is exchanged for extracellular calcium by the Na(+)/Ca(2+) exchanger resulting in calcium overload and damage to the myocardium. Numerous inhibitors of NHE have been developed to attempt to break this cycle of calcium overload. In animal models excellent success has been obtained in this regard. However in humans, clinical trials have resulted in only modest success and recently, significant detrimental side effects were note of one NHE inhibitor. The mechanisms by which these inhibitors affect NHE activity are presently being investigated and regions of the protein important in NHE activity and inhibitor efficacy are related but not identical. Future studies may develop superior inhibitors that may circumvent recently reported side effects. Recently, NHE inhibition has been shown to be remarkably effective in preventing hypertrophy in some animal models. Whether this proves to be a practical treatment for hypertrophy in humans has yet to be determined.

Mitogen-activated Protein Kinase-dependent Activation of the Na+/H+ Exchanger Is Mediated through Phosphorylation of Amino Acids Ser770 and Ser771

“…In mammals, NHE1 plays a key role in regulation of cell pH, cell volume, and cell proliferation and in the metastasis of some types of tumor cells (1,3). In the myocardium the Na ϩ /H ϩ exchanger plays a critical role in mediating the damage that occurs with ischemia/reperfusion of the heart (4 -6) and also is an important mediator of myocardial hypertrophy (7). Clinical trials are attempting to develop NHE1 inhibitors for treatment of various forms of heart disease (8).…”

Excessive Na+/H+ Exchange in Disruption of Dendritic Na+ and Ca2+ Homeostasis and Mitochondrial Dysfunction following in Vitro Ischemia

“…NHE-1 activity is directly activated by intracellular acidification and/or by protein phosphorylation mediated by ERK-p90 ribosomal S6 kinase (p90 RSK ) 2 in ischemic neurons (8). Excessive NHE-1 activation results in intracellular Na ϩ accumulation, which subsequently promotes Ca 2ϩ entry via reversal of Na ϩ /Ca 2ϩ exchange (NCX rev ) and plays an important role in myocardium ischemia/reperfusion injury (9). We recently reported that NHE-1 activity in the soma of neurons and astrocytes is stimulated following ischemia, and inhibition of NHE-1 activity is neuroprotective (8,10).…”

Pharmacodynamic characteristics and cardioprotective effects of new NHE1 inhibitors

“…Although its underlying molecular mechanisms are not yet clearly understood, the mechanisms associated with NHE1 function are emerging as promising targets for drug discovery (Fliegel and Karmazyn, 2004;Karmazyn et al, 2005). NHE1 inhibitors have been shown to exert protective effects on cardiac injuries both in vitro and in animal studies (Masereel et al, 2003).…”

“…During ischemia, ATP in the cardiac myocytes is drained and anaerobic glycolysis is accelerated, resulting in an increase in intracellular lactate and proton concentrations (Murry et al, 1986 (Karmazyn et al, 2005;Mentzer et al, 2003). Intracellular Ca 2+ overloads are associated with arrhythmias and contractile failure in cardiac cells in addition to the common cellular injuries (Lee et al, 2005b;Mentzer et al, 2003).…”

“…Accordingly, inhibition of NHE1 activation has been shown to protect the heart from various myocardial injuries (Fliegel and Karmazyn, 2004;Mentzer et al, 2003). In the last decade, several monocyclic acylguanidines like cariporide, eniporide, and zoniporide have been identified as selective and potent NHE1 inhibitors (Chen et al, 2001;Karmazyn et al, 2005;Knight et al, 2001;Masereel et al, 2003). While all these inhibitors showed protective effects against cardiac ischemia and reperfusion injuries under experimental conditions, their clinical utility in treating cardiac injury is presently not available.…”