Cardiac Sodium–Calcium Exchanger Expression

Abstract

The sodium-calcium exchanger (NCX) is thought to be a critical protein in excitation-contraction (E-C) 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, hypertension, cardiac hypertrophy, and heart failure. Therefore, it has the potential of being 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. Initially, therefore, the role of NCX in ischemic injury was elucidated with the use of blockers of the Na+-H+ exchanger, an upstream component of the NCX in the ischemia-reperfusion pathway. These drugs effectively inhibited the Na+-H+ exchange-NCX cascade during ischemia and early reperfusion to provide cardioprotection in isolated hearts and cardiomyocytes. Alternatively, the development of new genetic tools to increase or down-regulate the expression of the NCX has effectively characterized the role of the NCX in contractile activity and during ischemic injury. Compared to alternative molecular approaches to alter gene expression, the adenovirally delivered shRNA has been the most efficient method to alter gene expression in vitro. Cardiomyocytes with significantly depleted NCX through adenovirally delivered shRNA can still contract but are cardioprotected from ischemic insult. Furthermore, the cardiac isoform NCX1.1 causes more severe Ca2+ overload during ischemia-reperfusion injury and glycoside toxicity than the renal NCX1.3 isoform of the exchanger when they are expressed in neonatal cardiomyocytes and HEK-293 cells. In summary, the data support an important but not a critical role for NCX in excitation-contraction coupling in the heart but an important, possibly critical role, for the NCX in ischemic reperfusion injury 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.