Abstract:
:In the human heart several isoforms of the sodium pump (Na,K-ATPase, the cardiac glycoside receptor) are expressed (alpha1beta1, alpha2beta1, and alpha3beta1). 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 alpha2beta1 than for alpha1beta1 or alpha3beta1. In addition, alpha3beta1 had a lower turnover rate than alpha1beta1. 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 alpha1 or alpha2 isoforms were selectively reduced, only the lower expression and activity of alpha2 led to a hypercontractile response as seen with cardiac glycosides. Therefore in mice, the effect of cardiac glycosides seems to be mediated specifically by alpha2. 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.
journal_name
Basic Res Cardioljournal_title
Basic research in cardiologyauthors
Müller-Ehmsen J,McDonough AA,Farley RA,Schwinger RHdoi
10.1007/s003950200025keywords:
subject
Has Abstractpub_date
2002-01-01 00:00:00pages
I25-30eissn
0300-8428issn
1435-1803journal_volume
97 Suppl 1pub_type
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