Sodium pump isoform expression in heart failure: implication for treatment

Abstract

In the human heart several isoforms of the sodium pump (Na,K-ATPase, the cardiac glycoside receptor) are expressed (α1β1, α2β1, and α3β1). Their expression is regulated in a highly specific manner, so that there are region specific differences in the expression pattern. The isoform expression pattern is also known to be organ specific in many cases (e.g., kidney, skeletal muscle), suggesting isoform specific functions. In human heart, we have demonstrated that the isoform composition of the left ventricle is altered during heart failure in man and postulate a role of Na,K-ATPase isoforms in the compensatory mechanisms of this disease. When Na,K-ATPase isoforms were expressed separately in yeast cells, we found that the affinities of K and ouabain were lower for α2β1 than for α1β1 or α3β1. In addition, α3β1 had a lower turnover rate than α1β1. Similar results were found in a study, where Na,K-ATPase isoforms were expressed in Xenopus oocytes. Thus, there is evidence for specific biochemical properties of the Na,K-ATPase isoforms. In heterozygous knock-out mice, in which either α1 or α2 isoforms were selectively reduced, only the lower expression and activity of α2 led to a hypercontractile response as seen with cardiac glycosides. Therefore in mice, the effect of cardiac glycosides seems to be mediated specifically by α2.

In summary, there is a tissue-specific regulation of Na,K-ATPase isoform expression in humans, as well as a highly specific regulation of the isoforms during disease, e.g., heart failure. There is also evidence for specific biochemical properties of different isoforms of the human Na,K-ATPase as well as for a specific functional impact on cardiac contractility in mice. Therefore, the isoforms of human Na,K-ATPase are not exchangeable and targeting specific isoforms by drugs or gene therapy may promise therapeutic benefit in diseases like heart failure or atrial fibrillation.