The myocardial Na(+)-H(+) exchange: structure, regulation, and its role in heart disease.
The Na(+)-H(+) exchange (NHE) is a major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion. There are at least 6 NHE isoforms thus far identified with the NHE1 subtype representing the major one found in the mammalian myocardium. This 110-kDa glycoprotein extrudes protons concomitantly with Na(+) influx in a 1:1 stoichiometric relationship rendering the process electroneutral, and its activity is regulated by numerous factors, including phosphorylation-dependent processes. There is convincing evidence that NHE mediates tissue injury during ischemia and reperfusion, which probably reflects the fact that under conditions of tissue stress, including ischemia, Na(+)-K(+) ATPase is inhibited, thereby limiting Na(+) extrusion, resulting in an elevation in [Na(+)](i). The latter effect, in turn, will increase [Ca(2+)](i) via Na(+)-Ca(2+) exchange. In addition, NHE1 mRNA expression is elevated in response to injury, which may further contribute to the deleterious consequence of pathological insult. Extensive studies using NHE inhibitors have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and has led to clinical evaluation of NHE inhibition in patients with coronary artery disease. Emerging evidence also implicates NHE1 in other cardiac disease states, and the exchanger may be particularly critical to postinfarction remodeling responses resulting in development of hypertrophy and heart failure.
Karmazyn
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M
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada. mkarm@julian.uwo.ca
Gan
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Humphreys
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Yoshida
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Kusumoto
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D000818:Animals; D006321:Heart / Q000502:physiology*; D006331:Heart Diseases / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D017136:Ion Transport / Q000502:physiology; D020033:Protein Isoforms / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology*
D020033:Protein Isoforms; D017923:Sodium-Hydrogen Exchangers