Abstract
Ouabain is of cardiotonic steroids (CTS) family that is plant-derived compounds and is known for many years as therapeutic and cytotoxic agents. They are specific inhibitors of Na,K-ATPase, the enzyme, which pumps Na+ and K+ across plasma membrane of animal cells. Treatment of cells by CTS affects various cellular functions connected with the maintenance of the transmembrane gradient of Na+ and K+. Numerous studies demonstrated that binding of CTS to Na,K-ATPase not only suppresses its activity but also induces some signal pathways. This review is focused on different mechanisms of two ouabain effects: their ability (1) to protect rodent cells from apoptosis through the expression of [Na+]i-sensitive genes and (2) to trigger death of non-rodents cells (so-called «oncosis»), possessing combined markers of «classic» necrosis and «classic» apoptosis. Detailed study of oncosis demonstrated that the elevation of the [Na+]i/[K+]i ratio is not a sufficient for its triggering. Non-rodent cell death is determined by the characteristic property of “sensitive” to ouabain α1-subunit of Na,K-ATPase. In this case, ouabain binding leads to enzyme conformational changes triggering the activation of p38 mitogen-activated protein kinases (MAPK) signaling. The survival of rodent cells with ouabain-«resistant» α1-subunit is connected with another conformational transition induced by ouabain binding that results in the activation of ERK 1/2 signaling pathway.
Highlights
Olga Dmitrievna Lopina1, Artem Mikhaylovich Tverskoi 2,3*, Elizaveta Andreevna Klimanova1, Svetlana Vadimovna Sidorenko1 and Sergei Nikolaevich Orlov 3
Later on, employing Affymetrix-based technology, we revealed up to 60-fold changes in the expression of hundreds genes in rat vascular smooth muscle cells (RVSMC), human umbilical vein endothelial cells (HUVEC), human adenocarcinoma cell line (HeLa; Koltsova et al, 2012), mouse myoblast C2C12 cell line, rat aorta endothelial cells (RAEC), and primary cultured rat neurones subjected to NKA inhibition by ouabain (Klimanova et al, 2019a)
We observed that LDH release began when the volume of hyposmotically-swollen Madin-Darby canine kidney (MDCK) cells was augmented by ~5-fold. These results show that the rupture of the plasma membrane in ouabain-treated MDCK cells was not induced directly by cell swelling resulted from the NKA inhibition and inversion of the [Na+]i/[K+]i ratio (Platonova et al, 2011)
Summary
In all types of cells studied up to date, cell shrinkage is considered as the earliest marker of apoptosis (Bortner and Cidlowski, 1998; Lang and Hoffmann, 2012), in serum-deprived rat vascular smooth muscle cells (RVSMC; Orlov et al, 1996). We observed that antiapoptotic effect of ouabain entirely abolished by the decrease of the monovalent cations transmembrane gradient (Orlov et al, 1999) These results let us to the conclusion that inhibition of NKA protected RVSMC against apoptosis providing for the increase of the [Na+]i/[K+]i ratio. To investigate further Na+i-mediated antiapoptotic pathway, we employed inhibitors of RNA and protein synthesis (actinomycin D and cycloheximide, respectively) Both compounds eliminated protection against apoptosis observed in ouabain-treated RVSMC (Orlov et al, 1999). We observed that LDH release began when the volume of hyposmotically-swollen MDCK cells was augmented by ~5-fold These results show that the rupture of the plasma membrane in ouabain-treated MDCK cells was not induced directly by cell swelling resulted from the NKA inhibition and inversion of the [Na+]i/[K+]i ratio (Platonova et al, 2011)
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