期刊
APOPTOSIS
卷 20, 期 9, 页码 1200-1210出版社
SPRINGER
DOI: 10.1007/s10495-015-1144-y
关键词
Na+/K+ pump; Ouabain; Intracellular Na and K; Cell death
资金
- Russian Foundation for Fundamental Research [09-0073/04, 14-04-31705, 15-04-00101]
- Russian Scientific Foundation [14-15-00006]
- National Institutes of Health [NS061953]
- American Heart Association [14PRE18360017]
- Russian Science Foundation [14-15-00006] Funding Source: Russian Science Foundation
In rodents, ubiquitous alpha 1-Na+, K+-ATPase is inhibited by ouabain and other cardiotonic steroids (CTS) at similar to 10(3)-fold higher concentrations than those effective in other mammals. To examine the specific roles of the CTS-sensitive alpha 1S- and CTS-resistant alpha 1R-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 mu M ouabain dramatically increased the intracellular [Na+]/[K+] ratio to the same extend as in RASMC and RAEC treated with 3000 mu M ouabain. In 24, 3 mu M 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 mu M ouabain on the survival of rat cells, or smooth muscle cells from mouse aorta (MASMC). Unlike in the wild-type alpha 1(R/R) mouse, ouabain triggered death of MASMC from alpha 1(S/S) mouse expressing human alpha 1-Na+, K+-ATPase. Furthermore, transfection of HUVEC with rat alpha 1R-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 action of ouabain on human and rodent cells are caused by unique features of alpha 1S/alpha 1R-Na+, K+-ATPase, rather than by any downstream CTS-sensitive/resistant components of the cell death machinery.
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