Karmazyn M, Gan X T, Humphreys R A, Yoshida H, Kusumoto K
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada.
Circ Res. 1999 Oct 29;85(9):777-86. doi: 10.1161/01.res.85.9.777.
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(+). The latter effect, in turn, will increase Ca(2+) 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.
钠氢交换体（NHE）是心脏在缺血期间适应细胞内酸中毒并在再灌注后从酸中毒中恢复的主要机制。迄今为止，已鉴定出至少6种NHE亚型，其中NHE1亚型是在哺乳动物心肌中发现的主要亚型。这种110 kDa的糖蛋白以1:1的化学计量关系伴随着钠离子内流排出质子，使该过程呈电中性，其活性受多种因素调节，包括磷酸化依赖性过程。有确凿证据表明，NHE在缺血和再灌注期间介导组织损伤，这可能反映了在包括缺血在内的组织应激条件下，钠钾ATP酶受到抑制，从而限制了钠离子的排出，导致细胞内钠离子浓度升高。后者又会通过钠钙交换增加细胞内钙离子浓度。此外，NHE1 mRNA表达在损伤后升高，这可能进一步导致病理损伤的有害后果。使用NHE抑制剂的广泛研究一致表明，在多种实验模型中，其对缺血和再灌注损伤具有保护作用，并已导致对冠心病患者进行NHE抑制的临床评估。新出现的证据还表明NHE1与其他心脏疾病状态有关，并且该交换体可能对梗死后重塑反应特别关键，从而导致肥大和心力衰竭的发展。
