Karmazyn M, Sawyer M, Fliegel L
Department of Biochemistry, 347 Medical Sciences Building, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Curr Drug Targets Cardiovasc Haematol Disord. 2005 Aug;5(4):323-35. doi: 10.2174/1568006054553417.
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.
钠氢交换体（NHE）是一种存在于哺乳动物细胞中的普遍蛋白质。在高等真核生物中，这种整合膜蛋白将一个细胞内氢离子与一个细胞外钠离子进行交换，从而保护细胞免受细胞内酸化的影响。NHE在心肌中至关重要。它可防止抑制心肌收缩力的细胞内酸中毒。NHE在心肌缺血和再灌注期间发生的哺乳动物心肌损伤中也起关键作用，并且参与心肌肥大过程。NHE由一个约500个氨基酸的膜结合结构域加上一个约315个氨基酸的亲水性调节细胞质结构域组成。NHE1亚型是心肌中唯一重要的质膜亚型。在心肌梗死动物模型和左心室肥大中，NHE1的活性升高。在心肌缺血和再灌注期间，NHE活性催化细胞内钠摄取增加。这反过来又通过钠钙交换体与细胞外钙进行交换，导致钙超载和心肌损伤。已经开发了许多NHE抑制剂来试图打破这种钙超载循环。在这方面，在动物模型中已取得了显著成功。然而在人类中，临床试验仅取得了一定程度的成功，最近还注意到一种NHE抑制剂有明显的有害副作用。目前正在研究这些抑制剂影响NHE活性的机制，并且NHE活性和抑制剂疗效中重要的蛋白质区域相关但并不相同。未来的研究可能会开发出能避免最近报道的副作用的更优抑制剂。最近，已证明NHE抑制在某些动物模型中预防肥大非常有效。这是否被证明是人类肥大的一种实际治疗方法还有待确定。
