Cardioprotection in ischemia-reperfusion injury achieved by a single amino acid substitution of NCX1 (H165A)

We used genetically modified mice to test the hypothesis that pH regulation of the cardiac sodium calcium-exchanger (NCX1) contributes to ischemia/reperfusion (I/R) injury. NCX1 is the dominant calcium (Ca) efflux mechanism of cardiomyocytes and is strongly regulated by pH. During ischemia, when pH is lowered by anaerobic glycolysis, inhibition of NCX1 by acidosis may potentiate the Na overload imposed by Na/K pump failure and Na-H exchange. Upon reperfusion and restoration of normal pH, this high intracellular Na concentration drives the now functional NCX1 into reverse mode resulting in Ca overload.