Critical role of the α1-Na + , K + -ATPase subunit in insensitivity of rodent cells to cytotoxic action of ouabain

Abstract In rodents, ubiquitous α1-Na+, K+-ATPase is inhibited by ouabain and other cardiotonic steroids (CTS) at ~103-fold higher concentrations than those effective in other mammals. To examine the specific roles of the CTS-sensitive α1S- and CTS-resistant α1R-Na+, K+-ATPase isoforms, we compared the effects of ouabain on intracellular Na+ and K+ content, cell survival, and mitogen-activated protein kinases (MAPK) in human and rat vascular smooth muscle cells (HASMC and RASMC), human and rat endothelial cells (HUVEC and RAEC), and human and rat brain astrocytes. 6-h exposure of HASMC and HUVEC to 3 μM ouabain dramatically increased the intracellular [Na+]/[K+] ratio to the same extend as in RASMC and RAEC treated with 3000 μM ouabain. In 24, 3 μM ouabain triggered the death of all types of human cells used in this study. Unlike human cells, we did not detect any effect of 3000–5000 μM ouabain on the survival of rat cells, or smooth muscle cells from mouse aorta (MASMC). Unlike in the wild-type α1R/R mouse, ouabain triggered death of MASMC from α1S/S mouse expressing human α1-Na+, K+-ATPase. Furthermore, transfection of HUVEC with rat α1R-Na+, K+-ATPase protected them from the ouabain-induced death. In HUVEC, ouabain led to phosphorylation of p38 MAPK, whereas in RAEC it stimulated phosphorylation of ERK1/2. Overall, our results, demonstrate that the drastic differences in cytotoxic acti...
Source: Apoptosis - Category: Molecular Biology Source Type: research

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