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Effects of Ouabain on Proliferation of Human Endothelial Cells Correlate with Na+,K+-ATPase Activity and Intracellular Ratio of Na+ and K+

A. M. Tverskoi1, S. V. Sidorenko1, E. A. Klimanova1, O. A. Akimova1, L. V. Smolyaninova1, O. D. Lopina1, and S. N. Orlov1,2,3*

1Lomonosov Moscow State University, Faculty of Biology, 119991 Moscow, Russia; E-mail: sergeinorlov@yandex.ru

2Tomsk National Research State University, 634050 Tomsk, Russia

3Siberian State Medical University, 634050 Tomsk, Russia

* To whom correspondence should be addressed.

Received March 10, 2016; Revision received May 3, 2016
Side-by-side with inhibition of the Na+,K+-ATPase ouabain and other cardiotonic steroids (CTS) can affect cell functions by mechanisms other than regulation of the intracellular Na+ and K+ ratio ([Na+]i/[K+]i). Thus, we compared the dose- and time-dependences of the effect of ouabain on intracellular [Na+]i/[K+]i ratio, Na+,K+-ATPase activity, and proliferation of human umbilical vein endothelial cells (HUVEC). Treatment of the cells with 1-3 nM ouabain for 24-72 h decreased the [Na+]i/[K+]i ratio and increased cell proliferation by 20-50%. We discovered that the same ouabain concentrations increased Na+,K+-ATPase activity by 25-30%, as measured by the rate of 86Rb+ influx. Higher ouabain concentrations inhibited Na+,K+-ATPase, increased [Na+]i/[K+]i ratio, suppressed cell growth, and caused cell death. When cells were treated with low ouabain concentrations for 48 or 72 h, a negative correlation between [Na+]i/[K+]i ratio and cell growth activation was observed. In cells treated with high ouabain concentrations for 24 h, the [Na+]i/[K+]i ratio correlated positively with proliferation inhibition. These data demonstrate that inhibition of HUVEC proliferation at high CTS concentrations correlates with dissipation of the Na+ and K+ concentration gradients, whereas cell growth stimulation by low CTS doses results from activation of Na+,K+-ATPase and decrease in the [Na+]i/[K+]i ratio.
KEY WORDS: proliferation, endothelium, Na+,K+-ATPase, ouabain, intracellular Na+ and K+

DOI: 10.1134/S0006297916080083