Protection of the Myocardium During Ischemia and Reperfusion

Avkiran, Metin

doi:10.1161/01.cir.100.25.2469

Cited by 17 publications

(3 citation statements)

References 28 publications

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“…While the transmembrane region is necessary and sufficient for the ion-transport process, the cytosolic loop is involved in the regulation of the isoform's activities by mitogens and hormones (). The contribution of the Na + /H + exchangers in numerous pathophysiological situations has been hypothesized and documented, for example, in hypertension ( , ), post-ischemic myocardial arrhythmia ( − ), and regulation of the aqueous humor secretion associated with glaucoma (). Due to their properties, the Na + /H + exchangers are promising targets for structure function studies.…”

mentioning

confidence: 99%

Second-Site Revertants of a Low-Sodium-Affinity Mutant of the Na⁺/H⁺ Exchanger Reveal the Participation of TM4 into a Highly Constrained Sodium-Binding Site

2001

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On the basis of intracellular acidifications in the presence of 30 microM cariporide, we selected a fibroblast cell line termed CR5, expressing a mutated Na(+)/H(+) exchanger NHE-1 with a low affinity for cariporide (87 +/- 11.6 microM) and extracellular sodium (248 +/- 63.7 mM). This mutated exchanger displays a Phe162Ser substitution in its fourth transmembrane segment. Using intracellular acidifications in the presence of 3 mM external sodium on the CR5 fibroblasts, we isolated two revertants which exhibited a complete recovery for sodium affinity but were still resistant to cariporide. Sequencing the cDNAs encoding these revertants revealed the presence of two mutations situated at a distant location from Phe162 in the same fourth transmembrane segment (Ile169Ser and Ile170Thr). Interestingly, introducing these two mutations in the wild-type cDNA did not result in a significant increase in affinity for sodium. Furthermore, all the mutants characterized in this study display an unchanged affinity for lithium, another transported cation. These data suggest that the mutation resulting in the low sodium affinity and the two mutations responsible for the reversion of this phenotype affect the binding of sodium itself instead of the conformational changes triggering substrate translocation. Taken together, these results allow us to propose that optimal sodium binding by the Na(+)/H(+) exchangers requires the geometrical integrity of a highly constrained sodium coordination site.

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confidence: 99%

Second-Site Revertants of a Low-Sodium-Affinity Mutant of the Na⁺/H⁺ Exchanger Reveal the Participation of TM4 into a Highly Constrained Sodium-Binding Site

2001

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“…Accumulation of H + in the extra-cellular space inactivates NHE but washing out during reperfusion reactivates NHE, leading to unfavorably fast restoration of pHi and subsequent to Na + /Ca +2 exchange. High intracellular Ca +2 is assumed to be one of the main reasons for the ischemia and reperfusion injury like arrhythmia, myocardial contracture, stunning and necrosis (1,9,16,27,30). In addition, Na + /H + exchange has been shown to participate in the activation of both platelets and neutrophils, factors widely acknowledged participating in ischemia and reperfusion injury (13).…”

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confidence: 99%

“…Inhibition of NHE can interrupt processes at an early phase and prevent or delay the consequences of ischemia and reperfusion as it has been largely demonstrated (1,27 …”

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confidence: 99%

A halocin acting on Na+/H+ exchanger of Haloarchaea as a new type of inhibitor in NHE of mammals

Lequerica¹,

O’Connor

Such

et al. 2006

J. Physiol. Biochem.

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The capability of halocin H6 (a bacteriocin-like protein produced by haloarchaea Haloferax gibbonsii) to inhibit Na+/H+ exchanger (NHE) in mammalian cells and its cardio-protective efficacy on the ischemic and reperfused myocardium were evaluated in the present study. H6 inhibits NHE activity (measured by a flow cytometry method) in a dose-dependent form of cell lines of mammalian origin (HEK293, NIH3T3, Jurkat and HL-1) as well as in primary cell culture from human skeletal muscle (myocytes and fibroblasts). In vivo, an ischemia-reperfusion model in dogs by coronary arterial occlusion was used (two hours of regional ischemia and three hours of reperfusion). In animals treated with halocin H6 there was a significant reduction of premature ventricular ectopic beats and infarct size, whereas blood pressure and heart rate remained unchanged. Up to date, halocin H6 is the only described biological molecule that exerts a specific inhibitory activity in NHE of eukaryotic cells.

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Na/H Exchange and Arrhythmia

Hashimoto

Nagasawa

Zhu

2003

Myocardial Ischemia and Preconditioning

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Protection of the Myocardium During Ischemia and Reperfusion

Cited by 17 publications

References 28 publications

Second-Site Revertants of a Low-Sodium-Affinity Mutant of the Na⁺/H⁺ Exchanger Reveal the Participation of TM4 into a Highly Constrained Sodium-Binding Site

Second-Site Revertants of a Low-Sodium-Affinity Mutant of the Na⁺/H⁺ Exchanger Reveal the Participation of TM4 into a Highly Constrained Sodium-Binding Site

A halocin acting on Na+/H+ exchanger of Haloarchaea as a new type of inhibitor in NHE of mammals

Na/H Exchange and Arrhythmia

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Protection of the Myocardium During Ischemia and Reperfusion

Cited by 17 publications

References 28 publications

Second-Site Revertants of a Low-Sodium-Affinity Mutant of the Na+/H+ Exchanger Reveal the Participation of TM4 into a Highly Constrained Sodium-Binding Site

Second-Site Revertants of a Low-Sodium-Affinity Mutant of the Na+/H+ Exchanger Reveal the Participation of TM4 into a Highly Constrained Sodium-Binding Site

A halocin acting on Na+/H+ exchanger of Haloarchaea as a new type of inhibitor in NHE of mammals

Na/H Exchange and Arrhythmia

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Product

Resources

About

Second-Site Revertants of a Low-Sodium-Affinity Mutant of the Na⁺/H⁺ Exchanger Reveal the Participation of TM4 into a Highly Constrained Sodium-Binding Site

Second-Site Revertants of a Low-Sodium-Affinity Mutant of the Na⁺/H⁺ Exchanger Reveal the Participation of TM4 into a Highly Constrained Sodium-Binding Site