Wang Yigang, Meyer Jamie W, Ashraf Muhammad, Shull Gary E
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine,Cincinnati, Ohio, USA.
Circ Res. 2003 Oct 17;93(8):776-82. doi: 10.1161/01.RES.0000094746.24774.DC. Epub 2003 Sep 11.
Pharmacological studies indicate that Na+-H+ exchanger isoform 1 (NHE1) plays a central role in myocardial ischemia-reperfusion injury; however, confirmation by alternative methods is lacking. To address this issue, we examined the role of NHE1 in ischemia-reperfusion injury using gene-targeted NHE1-null mutant (Nhe1-/-) mice. Nhe1-/- and wild-type hearts were perfused in a Langendorff apparatus in both the absence and presence of the NHE1 inhibitor eniporide, subjected to 40 minutes of ischemia and 30 minutes of reperfusion, and the effects of genetic ablation or inhibition of NHE1 on hemodynamic, biochemical, and pathological changes were assessed. In the absence of eniporide, left ventricular developed pressure, end-diastolic pressure, and coronary flow were significantly less impaired in Nhe1-/- hearts relative to wild-type hearts, and release of lactate dehydrogenase, morphological damage, and ATP depletion were also significantly less. In the presence of eniporide, however, wild-type hearts were significantly protected and there were no significant differences between the two genotypes with respect to cardiac performance, lactate dehydrogenase release, or morphological damage. Furthermore, the presence or absence of eniporide had no apparent effect on the degree of cardioprotection observed in Nhe1-/- hearts. These data demonstrate that genetic ablation of NHE1 protects the heart against ischemia-reperfusion injury. In addition to providing direct evidence that confirms previous pharmacological studies indicating a role for NHE1 in ischemia-reperfusion injury, these results suggest that the long-term absence of NHE1 does not elicit major compensatory changes that might negate the cardioprotective effects of blocking its activity over the short-term.
药理学研究表明，钠氢交换体1型（NHE1）在心肌缺血再灌注损伤中起核心作用；然而，缺乏其他方法的证实。为解决这一问题，我们使用基因靶向的NHE1基因敲除突变体（Nhe1-/-）小鼠研究了NHE1在缺血再灌注损伤中的作用。在有无NHE1抑制剂依普利酮的情况下，将Nhe1-/-和野生型心脏在Langendorff装置中进行灌注，使其经历40分钟的缺血和30分钟的再灌注，并评估NHE1基因敲除或抑制对血流动力学、生化和病理变化的影响。在没有依普利酮的情况下，相对于野生型心脏，Nhe1-/-心脏的左心室舒张末压、舒张末期压力和冠状动脉流量受损明显较轻，乳酸脱氢酶的释放、形态损伤和ATP消耗也明显较少。然而，在有依普利酮的情况下，野生型心脏得到了显著保护，两种基因型在心脏功能、乳酸脱氢酶释放或形态损伤方面没有显著差异。此外，依普利酮的存在与否对Nhe1-/-心脏中观察到的心脏保护程度没有明显影响。这些数据表明，NHE1基因敲除可保护心脏免受缺血再灌注损伤。除了提供直接证据证实先前的药理学研究表明NHE1在缺血再灌注损伤中的作用外，这些结果还表明，长期缺乏NHE1不会引发可能抵消短期阻断其活性的心脏保护作用的主要代偿性变化。
