Published online before print September 11, 2003, doi: 10.1161/01.RES.0000094746.24774.DC
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Submitted on April 8, 2003
Revised on August 27, 2003
Accepted on August 28, 2003
Mice With a Null Mutation in the NHE1 Na+-H+ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury
Yigang Wang ;
From the Departments of Pathology and Laboratory Medicine (Y.W., M.A.) and Molecular Genetics, Biochemistry, and Microbiology (J.W.M., G.E.S.), University of Cincinnati College of Medicine, Cincinnati, Ohio.
* To whom correspondence should be addressed. E-mail: Muhammad.Ashraf{at}UC.Edu.
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.
Key words: Na+-H+ exchange • Slc9a1 • cariporide • ischemia • reperfusion
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