Overexpression of the Na+/H+ exchanger and ischemia-reperfusion injury in the myocardium

Kenichi Imahashi, Fatima Mraiche, Charles Steenbergen, Elizabeth Murphy, Larry Fliegel

Research output: Contribution to journalArticle

Abstract

In the myocardium, the Na+/H+ exchanger isoform-1 (NHE1) activity is detrimental during ischemia-reperfusion (I/R) injury, causing increased intracellular Na+ (Nai+) accumulation that results in subsequent Ca2+ overload. We tested the hypothesis that increased expression of NHE1 would accentuate myocardial I/R injury. Transgenic mice were created that increased the Na+/H + exchanger activity specifically in the myocardium. Intact hearts from transgenic mice at 10-15 wk of age showed no change in heart performance, resting intracellular pH (pHi) or phosphocreatine/ATP levels. Transgenic and wild-type (WT) hearts were subjected to 20 min of ischemia followed by 40 min of reperfusion. Surprisingly, the percent recovery of rate-pressure product (%RPP) after I/R improved in NHE1-overexpressing hearts (64 ± 5% vs. 41 ± 5% in WT; P < 0.05). In addition, NMR spectroscopy revealed that NHE1 overexpressor hearts contained higher ATP during early reperfusion (levels P < 0.05), and there was no difference in Na + accumulation during I/R between transgenic and WT hearts. HOE642 (cariporide), an NHE1 inhibitor, equivalently protected both WT and NHE1-overexpressing hearts. When hearts were perfused with bicarbonate-free HEPES buffer to eliminate the contribution of HCO3- transporters to pHi regulation, there was no difference in contractile recovery after reperfusion between controls and transgenics, but NHE1-overexpressing hearts showed a greater decrease in ATP during ischemia. These results indicate that the basal activity of NHE1 is not rate limiting in causing damage during I/R, therefore, increasing the level of NHE1 does not enhance injury and can have some small protective effects.

Original languageEnglish (US)
Pages (from-to)H2237-H2247
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number5
DOIs
StatePublished - May 1 2007

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Keywords

  • Intracellular pH
  • Intracellular sodium
  • Sodium/hydrogen exchange
  • Transgenic mice

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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