Background: Intracellular pH (pHi) is critical to cardiac excitation and contraction; uncompensated changes in pHi impair cardiac function and trigger arrhythmia. Recently, we have identified and cloned different isoforms of a solute carrier, Slc26a6, from cardiac myocytes (Kim HJ et al.Slc26a6 functions as an electrogenic Cl-/HCO3- exchanger in cardiac myocytes. Cardiovascular Research. 2013; 100: 383-391). Slc26a6 represents the key Cl-/HCO3- and Cl-/OH- exchanger in the heart critical in cardiac Cl- homeostasis and pHi regulation, which is one of the primary determinants of outcome in cardiac ischemia. We further demonstrate that cardiac Slc26a6 mediates electrogenic Cl-/HCO3- exchange activities. We hypothesize that Slc26a6 plays critical roles in cardiac ischemia/reperfusion (I/R) injury and ablation of Slc26a6 will result in a significant alteration in acid-base balance and Cl- homeostasis in cardiomyocytes during cardiac ischemia.
Methods and Results: To directly test the mechanistic role of Slc26a6 in cardiac ischemia, we took advantage of Slc26a6 knockout (Slc26a6-/-) mice using multidisciplinary in vivo and in vitro approaches, including functional electrophysiological recordings, sarcomere shortening measurement, imaging, biochemical, molecular, and genetic approaches. Indeed, ablation of Slc26a6 shortens action potential duration, impairs the contractility and increases pHiof cardiomyocytes. Moreover, using an I/R mouse model, we evaluated the functional role of cardiac Slc26a6 in response to I/R. We found significant differences in cardiac function regulation in response to I/R between Slc26a6-/- and wild type (WT) mouse models, suggesting the essential role of Slc26a6 in cellular damages from cardiac ischemia.
Conclusion: Our study provided the first evidence demonstrating the critical roles of Slc26a6 in cardiac pHi regulation and I/R injury. Slc26a6 may affect the pHi and cellular Cl- homeostasis during ischemia, as well as the rapid correction of intracellular acidosis during reperfusion, which represents one key action to reduce the reperfusion injury.