Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

Abstract

Abstract-Pharmacological studies indicate that Naϩ -H ϩ 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 Ϫ/Ϫ ) mice. Nhe1Ϫ/Ϫ 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 Ϫ/Ϫ 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 Ϫ/Ϫ 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.

The Basolateral NHE1 Na+/H+ Exchanger Regulates Transepithelial HCO3− Absorption through Actin Cytoskeleton Remodeling in Renal Thick Ascending Limb

“…An effect of NHE1 to control NHE3 or other transporters also may be relevant to pathophysiological conditions in which NHE1 expression and activity are altered. For example, increased NHE1 activity contributes to ischemic-reperfusion injury of myocardial cells, a process that involves regulatory interactions of NHE1 with other transporters such as Na ϩ / Ca 2ϩ exchange (50,51). Also, NHE1 activity is increased in a variety of cells and tissues in patients with essential hypertension and in hypertensive animal models (52,53), and transgenic mice overexpressing NHE1 exhibit salt-sensitive hypertension in association with renal Na ϩ retention (54).…”

Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl−/HCOPrasad1, Bódi2, Meyer3 et al. 2008Journal of Biological ChemistrySelf Cite296462View full textAdd to dashboardCite

“…Langendorff Heart Studies-Susceptibility of wild-type and AE3 null hearts (n ϭ 6 hearts/genotype) to impaired cardiac function resulting from I/R injury was analyzed using a Langendorff apparatus as described for the Na ϩ /H ϩ exchanger 1 knock-out (25), except that a 30-min period of no-flow ischemia was used.…”

“…Loss of AE3 Did Not Affect Ischemia-Reperfusion InjuryLoss of Na ϩ /H ϩ exchange or Na ϩ /HCO 3 Ϫ cotransport activity protects against I/R injury (19,25,34,35) by reducing the Na ϩ loading that leads to excess Ca 2ϩ loading. Because Cl Ϫ /HCO 3 Ϫ exchange can operate in concert with these acid extrusion mechanisms, thereby enhancing their activities, and has an opposite effect on pH i when operating alone, we analyzed the effect of the AE3 null mutation on I/R injury ( Ϫ/Ϫ and wild-type hearts, respectively) did not differ significantly between the two genotypes (n ϭ 6 for each genotype).…”

The Effect of the Antioxidant Drug “U-74389G” on Lactate Dehydrogenase Levels during Ischemia Reperfusion Injury in Rats

“…Hoeven et al [12] found progressive organ; particularly kidney dysfunction and inflammatory responses most pronounced in hemodynamically unstable brain-dead donors studied by monitoring LDH levels in Wistar rats. Wang et al evaluated [13] the released LDH levels significantly less impaired in gene-targeted NHE1-null mutant (Nhe1-/-) mice IR hearts relative to wild-type ones, in absence of NHE1 inhibitor. Wang et al [14] measured decreased release of skeletal muscle intracellular enzyme LDH in experimental groups protected by ischemic preconditioning (IP) in limb IR injury compared with the control ones.…”