Role of sodium-calcium exchange in cardiac physiology and pathophysiology

The sodium-calcium exchanger (NCX) is thought to be a critical protein in excitation-contraction coupling in the heart through its regulation of intracellular [Ca2+]. The exchanger removes Ca2+ from the cell in exchange for extracellular Na+ in the "forward mode" to induce cardiac relaxation. Although still controversial, NCX may also participate in cardiomyocyte contractile activity in a reverse mode by bringing Ca2+ into the cell in exchange for intracellular Na+. In addition to its important physiological role, the NCX has been associated with the pathology of ischemia-reperfusion injury, glycoside toxicity, cardiac hypertrophy and heart failure. Therefore, it be a valuable therapeutic target in the treatment of heart disease.; A limitation in the study of the exchanger has been the dearth of pharmacological blockers that specifically inhibit the NCX. I found that blockaged of the Na+-H+ exchanger, an upstream component of the NCX in the ischemia-reperfusion pathway, solely during early reperfusion can provide cardioprotection in isolated cardiomyocytes. We have also described the development of RNA interference, a new genetic tool, to down-regulate the expression of the NCX and characterized the effect of NCX depletion. We showed that neonatal cardiomyocytes with nominally depleted NCX through adenovirally delivered short hairpin RNA (shRNA) can still contract. When this new tool was compared to alternative approaches it was found to be highly efficient. The data support an important but not a critical role for NCX in excitation-contraction coupling in the heart. We also studied the function of the cardiac (NCX1.1) and renal (NCX1.3) isoforms of the exchanger, expressed in neonatal cardiomyocytes and HEK-293 cells, and found that the cardiac isoform causes more severe Ca 2+ overload during ischemia-reperfusion injury and glycoside toxicity. In summary, our results demonstrate that the NCX is important in defining contractile activity in the normal heart but it is not essential. It is also important in defining contractile dysfunction during ischemic and drug-induced challenges. Overall, these results identify NCX as an important molecule to target to develop new strategies to influence heart function and dysfunction.