Cardiotonic Steroids: Novel Mechanisms of Na+ i-Mediated and - Independent Signaling Involved in the Regulation of Gene Expression, Proliferation and Cell Death

Orlov, Sergei N.; Akimova, Olga A.; Hamet, Pavel

doi:10.2174/157340205774574559

Cited by 15 publications

(12 citation statements)

References 147 publications

(199 reference statements)

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“…Thus, side-by-side with C7-MDCK cells resembling principal cells from canine kidney collecting ducts, long-term exposure to ouabain led to massive death of intercalated-like C11-MDCK cells [10] and Caco-2 cells isolated from human colon rectal carcinoma [13]. In contrast, 48 h exposure to high doses of ouabain did not decrease survival of rVSMC [6] and NIH 3T3 mouse fibroblasts [13]. Here, we confirm these observations by chromatin cleavage assay in cells treated with ouabain for 24 h (Table 2).…”

Section: Resultsmentioning

confidence: 99%

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Death of ouabain-treated renal epithelial cells: evidence for p38 MAPK-mediated Na i + /K i + -independent signaling

et al. 2009

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Recent studies demonstrate that cytotoxic actions of ouabain and other cardiotonic steroids (CTS) on renal epithelial cells (REC) are triggered by their interaction with the Na(+),K(+)-ATPase alpha-subunit but not the result of inhibition of Na(+),K(+)-ATPase-mediated ion fluxes and inversion of the [Na(+)](i)/[K(+)](i) ratio. This study examined the role of mitogen-activated protein kinases (MAPK) in the death of ouabain-treated REC. Exposure of C7-MDCK cells that resembled principal cells from canine kidney to 3 microM ouabain led to phosphorylation of p38 without significant impact on phosphorylation of ERK and JNK MAPK. Maximal increment of p38 phosphorylation was observed at 4 h followed by cell death at 12 h of ouabain addition. In contrast to ouabain, neither cell death nor p38 MAPK phosphorylation were affected by elevation of the [Na(+)](i)/[K(+)](i) ratio triggered by Na(+),K(+)-ATPase inhibition in K(+)-free medium. p38 phosphorylation was noted in all other cell types exhibiting death in the presence of ouabain, such as intercalated cells from canine kidney and human colon rectal carcinoma cells. We did not observe any action of ouabain on p38 phosphorylation in ouabain-resistant smooth muscle cells from rat aorta and endothelial cells from human umbilical vein. Both p38 phosphorylation and death of ouabain-treated C7-MDCK cells were suppressed by p38 inhibitor SB 202190 but were resistant to its inactive analogue SB 202474. Our results demonstrate that death of CTS-treated REC is triggered by Na (i) (+) ,K (i) (+) -independent activation of p38 MAPK.

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Section: Resultsmentioning

confidence: 99%

“…i /[K ? ] i ratio (for review, see [13][14][15]). In a previous investigation, we failed to detect any involvement of PLC, Ca i 2?…”

Section: Introductionmentioning

confidence: 99%

Death of ouabain-treated renal epithelial cells: evidence for p38 MAPK-mediated Na i + /K i + -independent signaling

et al. 2009

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“…In accordance with this model, cell swelling per se is sufficient for plasma membrane damage to result in cell death [11]. It should be mentioned, however, that sharp elevation of the [Na + ] i /[K + ] i ratio detected in 24 h of ouabain addition did not affect the survival of renal epithelial cells from the Rhesus monkey [7,12], human lymphocytes [13], rat VSMC [2] and astrocytes (unpublished data) as well as NIH 3T3, HeLa and Caki cell lines [14].…”

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confidence: 90%

Modest intracellular acidification suppresses death signaling in ouabain-treated cells

Akimova

Pchejetski

Hamet

et al. 2005

Pflugers Arch - Eur J Physiol

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The signaling cascade resulting in the death of several types of cells treated with ouabain or other cardiotonic steroids (CTS) remains poorly understood. Recently, we observed that ouabain kills epithelial and endothelial cells via its interaction with Na(+), K(+) -ATPase, but independently of inhibition of Na(+), K(+) -ATPase-mediated ion fluxes and inversion of the [Na(+)](i)/[K(+)](i) ratio. Here, we report that the death of ouabain-treated epithelial cells from the Madin-Darby canine kidney (C7-MDCK) and endothelial cells from porcine aortae is suppressed by acidification of medium from pH 7.4 to 7.0, i.e. under conditions when pH(i) was decreased from approximately 7.2 to 6.9. The rescue of ouabain-treated C7-MDCK cells was also detected under selective intracellular acidification caused by inhibition of Na(+)/H(+) exchanger. In these cells, neither Na(+), K(+) pump activity nor [(3)H]-ouabain binding was significantly affected by modest acidification. The death of ouabain-treated cells was independent of inhibition of RNA and protein synthesis with actinomycin D and cycloheximide. In contrast, both compounds sharply attenuated the protective action of acidified medium. Thus, our results show that very modest intracellular acidification is sufficient to inhibit the Na(+) (i)/K(+) (i)-independent death signal triggered in epithelial and endothelial cells by CTS. They also suggest that the protective action of acidification is mediated by de novo expression of genes involved in inhibition of the cell death machinery.

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“…Thus, 24-h inhibition of Na + ,K + -ATPase with ouabain does not impact rat vascular smooth muscle cells (VSMC) [1,2], human lymphocytes [3], rat astrocytes [4] as well as HeLa, HEK-293, NIH 3T3 and Caki cell lines [5]. In contrast, the same treatment protocol leads to massive detachment and death of Madin-Darby canine kidney (MDCK) renal epithelial cells [6,7], porcine aorta endothelial cells [8], and human colon carcinoma Caco-2 cells [5]. Ouabain rescues rat serum-deprived VSMC from apoptosis [1,9,10] but results in apoptosis of neuronal-like NT2 cells [11] and epithelial-derived tumor cells [12,13].…”

Section: Introductionmentioning

confidence: 99%

The death of ouabain-treated renal epithelial cells: evidence against anoikis occurrence

et al. 2008

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The mechanisms of cell death signaling triggered by cardiotonic steroids are poorly understood. Based on massive detachment of ouabain-treated Madin-Darby canine kidney (MDCK) cells, it may be proposed that the cytotoxic action of these compounds is mediated by anoikis, i.e. a particular mode of death occurring in cells lacking cell-to-extracellular matrix interactions. We tested this hypothesis. Six hour incubation of MDCK cells with ouabain, marinobufagenin or K+-free medium almost completely blocked Na+,K+-ATPase, increased Na (i) + content by approximately 10-fold and suppressed cell attachment to regular-plastic-plates by up to 5-fold. In contrast, the death of attached cells was observed after 24-h incubation with ouabain but not in the presence of marinobufagenin or K+-free medium. Cells treated with ouabain and undergoing anoikis on ultra-low attachment plates exhibited different cell volume behaviour, i.e. swelling and shrinkage, respectively. The pan-caspase inhibitor z-VAD.fmk and the protein kinase C activator PMA rescued MDCK cells from anoikis but did not influence the survival of ouabain-treated cells, whereas medium acidification from pH 7.2 to 6.7 almost completely abolished the cytotoxic action of ouabain, but did not significantly affect anoikis. Our results show that the Na (i) + ,K (i) + -independent mode of MDCK cell death evoked by ouabain is not mediated by anoikis.

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Cardiotonic Steroids: Novel Mechanisms of Na+ i-Mediated and - Independent Signaling Involved in the Regulation of Gene Expression, Proliferation and Cell Death

Cited by 15 publications

References 147 publications

Death of ouabain-treated renal epithelial cells: evidence for p38 MAPK-mediated Na i + /K i + -independent signaling

Death of ouabain-treated renal epithelial cells: evidence for p38 MAPK-mediated Na i + /K i + -independent signaling

Modest intracellular acidification suppresses death signaling in ouabain-treated cells

The death of ouabain-treated renal epithelial cells: evidence against anoikis occurrence

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