Müller-Ehmsen Jochen, McDonough Alicia A, Farley Robert A, Schwinger Robert H G
Laboratory of Muscle Research and Molecular Cardiology, Clinic III for Internal Medicine, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany.
Basic Res Cardiol. 2002;97 Suppl 1:I25-30. doi: 10.1007/s003950200025.
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.
在人类心脏中，钠泵（Na，K - ATP酶，强心苷受体）有几种同工型表达（α1β1、α2β1和α3β1）。它们的表达以高度特异性的方式受到调控，因此在表达模式上存在区域特异性差异。在许多情况下，同工型表达模式在器官水平上也具有特异性（例如肾脏、骨骼肌），这表明同工型具有特定功能。在人类心脏中，我们已经证明，在人类心力衰竭期间左心室的同工型组成会发生改变，并推测Na，K - ATP酶同工型在这种疾病的代偿机制中发挥作用。当Na，K - ATP酶同工型在酵母细胞中单独表达时，我们发现α2β1对K和哇巴因的亲和力低于α1β1或α3β1。此外，α3β1的周转率低于α1β1。在一项将Na，K - ATP酶同工型在非洲爪蟾卵母细胞中表达的研究中也发现了类似结果。因此，有证据表明Na，K - ATP酶同工型具有特定的生化特性。在杂合敲除小鼠中，α1或α2同工型被选择性降低，只有α2的低表达和低活性会导致如强心苷所见的心肌收缩反应增强。因此在小鼠中，强心苷的作用似乎是由α2特异性介导的。总之，在人类中存在Na，K - ATP酶同工型表达的组织特异性调控，以及在疾病（如心力衰竭）期间同工型的高度特异性调控。也有证据表明人类Na，K - ATP酶不同同工型具有特定的生化特性，以及对小鼠心肌收缩力有特定的功能影响。因此，人类Na，K - ATP酶同工型不可互换，通过药物或基因疗法靶向特定同工型可能有望在心力衰竭或心房颤动等疾病中带来治疗益处。
