Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2H7, Canada.
J Mol Cell Cardiol. 2011 Jan;50(1):157-64. doi: 10.1016/j.yjmcc.2010.10.016. Epub 2010 Oct 23.
In the myocardium, the Na(+)/H(+) exchanger isoform 1 (NHE1) is a plasma membrane protein that regulates intracellular pH. Inhibition of NHE1 activity has been shown to be beneficial in cardiovascular disease. However, recent reports have suggested that elevation of NHE1 levels has beneficial effects in hearts subjected to ischemia/reperfusion. We determined if activated and non-activated NHE1 proteins have varying cardioprotective and metabolic effects with ischemia/reperfusion in the isolated perfused working mouse heart. We used transgenic mice hearts that specifically expressed wild type NHE1 (N-line) or activated NHE1 protein (K-line). Intact hearts 10-12 weeks of age were perfused under working conditions, with fatty acids and glucose present as substrates. Hearts were subjected to 30 min of aerobic perfusion, followed by 20 min of global no-flow ischemia and 40 min of aerobic reperfusion. We examined changes in contractility and substrate use and ATP levels. K-line hearts expressing activated NHE1, recovered to a much greater extent than N-line and control hearts recovering almost 75% of their preischemic function. In addition, K-line hearts had elevated fatty acid oxidation, increased glycolysis rates and elevated ATP levels relative to N-line mice or controls. An examination of kinase activation showed that there were no differences between controls and transgenics in ERK, p38, p90(rsk) or pGSK3β levels. The results demonstrate that elevated levels of NHE1 induce cardioprotection and alter cardiac metabolism. However, in the working heart model, with glucose and fatty acid as substrates, this required an activated NHE1 protein.
在心肌中，钠氢交换体 1（NHE1）异构体是一种调节细胞内 pH 值的质膜蛋白。抑制 NHE1 活性已被证明对心血管疾病有益。然而，最近的报告表明，NHE1 水平升高对缺血/再灌注的心脏具有有益作用。我们确定在分离的灌注工作的小鼠心脏中，激活和非激活的 NHE1 蛋白在缺血/再灌注时是否具有不同的心脏保护和代谢作用。我们使用专门表达野生型 NHE1（N 线）或激活的 NHE1 蛋白（K 线）的转基因小鼠心脏。10-12 周龄的完整心脏在工作条件下进行灌注，以脂肪酸和葡萄糖为底物。心脏经历 30 分钟的有氧灌注，随后进行 20 分钟的全流量无血流缺血和 40 分钟的有氧再灌注。我们检查了收缩性和底物利用以及 ATP 水平的变化。表达激活的 NHE1 的 K 线心脏的恢复程度远远大于 N 线和对照心脏，几乎恢复了缺血前功能的 75%。此外，与 N 线小鼠或对照相比，K 线心脏的脂肪酸氧化增加，糖酵解速率增加，ATP 水平升高。对激酶激活的检查表明，对照和转基因之间在 ERK、p38、p90（rsk）或 pGSK3β水平上没有差异。结果表明，NHE1 水平升高可诱导心脏保护并改变心脏代谢。然而，在工作心脏模型中，以葡萄糖和脂肪酸为底物，这需要激活的 NHE1 蛋白。
