Elevated levels of activated NHE1 protect the myocardium and improve metabolism following ischemia/reperfusion injury.

ABSTRACT

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 pGSK3ß 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.