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Review Article | Open Access

Na,K-ATPase as a target for endogenous cardiotonic steroids: What’s the evidence?

Sergei N. Orlova,b,c, Artem M. Tverskoia,( ), Svetlana V. Sidorenkoa,b, Larisa V. Smolyaninovaa,b, Olga D. Lopinaa, Nickolai O. Dulind, Elizaveta A. Klimanovaa,b
MV Lomonosov Moscow State University, Moscow, 119234, Russia
National Research Tomsk State University, Tomsk, 634050, Russia
Siberian State Medical University, Tomsk, 634050, Russia
University of Chicago, IL, 60637, USA

Peer review under responsibility of Chongqing Medical University.

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Abstract

With an exception of few reports, the plasma concentration of ouabain and marinobufagenin, mostly studied cardiotonic steroids (CTS) assessed by immunoassay techniques, is less than 1 nM. During the last 3 decades, the implication of these endogenous CTS in the pathogenesis of hypertension and other volume-expanded disorders is widely disputed. The threshold for inhibition by CTS of human and rodent α1-Na,K-ATPase is ~1 and 1000 nM, respectively, that rules out the functioning of endogenous CTS (ECTS) as natriuretic hormones and regulators of cell adhesion, cell-to-cell communication, gene transcription and translation, which are mediated by dissipation of the transmembrane gradients of monovalent cations. In several types of cells ouabain and marinobufagenin at concentrations corresponding to its plasma level activate Na,K-ATPase, decrease the [Na+]i/[K+]i-ratio and increase cell proliferation. Possible physiological significance and mechanism of non-canonical Nai+/Ki+-dependent and Nai+/Ki+-independent cell responses to CTS are discussed.

Keywords

TranslationCell proliferationTranscriptionCellular signalingEndogenous cardiotonic steroidsNa+,K+-ATPase

References

1

de Wardener HE, Mills IH, Clapham WF, Hayter CJ. Studies on the efferent mechanism of the sodium diuresis which follows the administration of intravenous saline in the dog. Clin Sci. 1961;21: 249-258.
Google Scholar
2

de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extracts in rats. Life Sci. 1981;28(1): 89-94.
Crossref Google Scholar
3

Buckalew VM, Martinez FJ, Green WE. The effect of dialysates and ultrafiltrates of plasma of saline-loaded dogs on toad bladder sodium transport. J Clin Invest. 1970;49(5): 926-935.
Crossref Google Scholar
4

Buckalew VM. Endogenous digitalis-like factors: an overview of the history. Front Endocrinol. 2015;6, e49.
Crossref Google Scholar
5

Hamlyn JM. Natriuretic hormones, endogenous ouabain, and related sodium transport inhibitors. Front Endocrinol. 2014;5, e199.
Crossref Google Scholar
6

Krenn L, Kopp B. Bufadienolides from animal and plant sources. Phytochemistry. 1998;48(1): 1-29.
Crossref Google Scholar
7

Hamlyn JM, Blaustein MP, Bova S, et al. Identification and characterization of a ouabain-like compound from human plasma. Proc Natl Acad Sci U S A. 1991;88(14): 6259-6263.
Crossref Google Scholar
8

Kawamura A, Guo J, Itagaki Y, et al. On the structure of endogenous ouabain. Proc Natl Acad Sci USA. 1999;96(12): 6654-6659.
Crossref Google Scholar
9

Schneider R, Wray V, Nimtz M, et al. Bovine adrenals contain, in addition to ouabain, a second inhibitor of the sodium pump. J Biol Chem. 1998;273(2): 784-792.
Crossref Google Scholar
10

Goto A, Ishiguro T, Yamada K, et al. Isolation of an urinary digitalis-like factor indistinguishable from digoxin. Biochem Biophys Res Commun. 1990;173(3): 1093-1101.
Crossref Google Scholar
11

Lichtstein D, Gati I, Samuelov S, et al. Identification of digitalis-like compounds in human cataractous lenses. Eur J Biochem. 1993;216(1): 261-268.
Crossref Google Scholar
12

Bagrov AY, Fedorova OV. Effects of two putative endogenous digitalis-like factors, marinobufagenin and ouabain, on the Na+, K+-pump in human mesenteric arteries. J Hypertens. 1998;16(12 Pt 2): 1953-1958.
Crossref Google Scholar
13

Bagrov AY, Fedorova OV, Dmitrieva RI, et al. Characterization of a urinary bufodielnolide Na, K-ATPase inhibitor in patients after acute myocardial infarction. Hypertension. 1998;31(5): 1097-1103.
Crossref Google Scholar
14

Komiyama Y, Dong XH, Hishimura N, et al. A novel endogenous digitalis, telocinobufagin, exhibits elevated plasma levels in patients with terminal renal failure. Clin Biochem. 2005;38(1): 36-45.
Crossref Google Scholar
15

Yoshika M, Komiyama Y, Konishi M, et al. Novel digitalis-like factor, marinobufotoxin, isolated from cultured Y-1 cells, and its hypertensive effect in rats. Hypertension. 2007;49(1): 209-214.
Crossref Google Scholar
16

Schoner W, Scheiner-Bobis G. Endogenous and exogenous cardiac glycosides: their role in hypertension, salt metabolism, and cell growth. Am J Physiol Cell Physiol. 2007;293(2): C509–C536.
Crossref Google Scholar
17

Bagrov AY, Shapiro JI, Fedorova OV. Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev. 2009;61(1): 9-38.
Crossref Google Scholar
18

Leenen FHH. The central role of the brain aldosterone-“ouabain” pathway in salt-sensitive hypertension. Biochim Biophys Acta. 2010;1802(12): 1132-1139.
Crossref Google Scholar
19

Hodes A, Lichtstein D. Natriuretic hormones in brain function. Front Endocrinol. 2014;5: 201.
Crossref Google Scholar
20

Khalaf FK, Dube P, Mohamed A, et al. Cardiotonic steroids and the sodium trade balance: new insights into trade-off mechanisms mediated by the Na+, K+-ATPase. Int J Mol Sci. 2018;19(9), e2576.
Crossref Google Scholar
21

Blaustein MP, Chen L, Hamlyn JM, et al. Pivotal role od a2 Na+ pumps and their high affinity ouabain binding site in cardiovascular health and disease. J Physiol. 2016;594(21): 6079-6103.
Crossref Google Scholar
22

Skou JC. Further investigation on a Mg2+ + Na+-activated adenosinetriphosphatase possibly related to the active transport of Na+ and K+ across the nerve cell membrane. Biochim Biophys Acta. 1960;42: 6-23.
Crossref Google Scholar
23

Dvela M, Rosen H, Feldmann T, Nesher M, Lichtstein D. Diverse biological responses of different cardiotonic steroids. Pathophysiology. 2007;14(3–4): 159-166.
Crossref Google Scholar
24

Xie Z, Xie J. The Na/K-ATPase-mediated signal transduction as a target for new drug development. Front Biosci. 2005;10: 3100-3109.
Crossref Google Scholar
25

Hamlyn JM, Blaustein MP. Endogenous ouabain: recent advances and controversies. Hypertension. 2016;68(3): 526-532.
Crossref Google Scholar
26

Doris PA, Jenkins LA, Stocco DM. Is ouabain an authentic endogenous mammalian substance derived from the adrenal? Hypertension. 1994;23(5): 632-638.
Crossref Google Scholar
27

Gomez-Sanchez EP, Poecking MF, Sellers D, Gomez-Sanches CE. Is the circulation ouabain-like compound ouabain? Am J Hypertens. 1994;7(7 Pt 1): 647-650.
Crossref Google Scholar
28

Lewis LK, Yandle TG, Lewis JG, et al. Ouabain is not detectable in human plasma. Hypertension. 2019;24(5): 549-555.
Crossref Google Scholar
29

Baecher S, Kroiss M, Fassnacht M, Vogeser M. No endogenous ouabain is detectable in human plasma by ultra-sensitive UPLC-MS/MS. Clin Chim Acta. 2014;431: 87-92.
Crossref Google Scholar
30

Clausen M, Hilbers F, Poulsen H. The structure and function of the Na, K-ATPase isoforms in health and disease. Front Physiol. 2017;8, e371.
Crossref Google Scholar
31

Lingrel JB, Croyle ML, Woo AL, Argьello JM. Ligand binding sites of Na, K-ATPase. Acta Physiol Scand. 1998;163(suppl. 643): 69-77.
Google Scholar
32

Lingrel JB. The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na, K-ATPase. Annu Rev Physiol. 2010;72: 395-412.
Crossref Google Scholar
33

Blaustein M. Sodium transport in hypertension. Where are we going? Hypertension. 1984;6(4): 445-453.
Crossref Google Scholar
34

Hauptman PJ, Garg R, Kelly RA. Cardiac glycosides in the next millennium. Prog Cardiovasc Dis. 1999;41(4): 247-254.
Crossref Google Scholar
35

Orlov SN, Taurin S, Hamet P. The α1-Na/K pump does not mediate the involvement of ouabain in the development of hypertension in rats. Blood Pres. 2002;11(1): 56-62.
Crossref Google Scholar
36

Fedorova OV, Bagrov AY. Inhibition of Na/K ATPase from rat aorta by two Na/K pump inhibitors, ouabain and marinobufagenin: evidence of interaction with different alpha-subunit isoform. Am J Hypertens. 1997;10(8): 929-935.
Crossref Google Scholar
37

Akimova OA, Bagrov AY, Lopina OD, et al. Cardiotonic steroids differentially affect intracellular Na+ and [Na+]i/[K+]i-independent signaling in C7-MDCK cells. J Biol Chem. 2005;280(1): 832-839.
Crossref Google Scholar
38

Klimanova EA, Petrushenko IY, Mitkevich VA, et al. Binding of ouabain and marinobufagenin leads to different structural changes in Na, K-ATPase and depends on the enzyme conformation. FEBS Lett. 2015;589(19 Pt B): 2668-2674.
Crossref Google Scholar
39

Blaustein MP, Zhang J, Chen L, Hamilton BP. How does salt retention raise blood pressure? Am J Physiol Regul Integr Comp Physiol. 2006;290(3): R514–R523.
Crossref Google Scholar
40

Iwamoto T, Kita S, Zhang J, et al. Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle cells. Nat Med. 2004;10(11): 1193-1199.
Crossref Google Scholar
41

Orlov SN, Taurin S, Tremblay J, Hamet P. Inhibition of Na+, K+ pump affects nucleic acid synthesis and smooth muscle cell proliferation via elevation of the [Na+]i/[K+]i ratio: possible implication in vascular remodeling. J Hypertens. 2001;19(9): 1559-1565.
Crossref Google Scholar
42

Taurin S, Seyrantepe V, Orlov SN, et al. Proteome analysis and functional expression identify mortalin as an anti-apoptotic gene induced by elevation of [Na+]i/[K+]i ratio in cultured vascular smooth muscle cells. Circ Res. 2002;91(10): 915-922.
Crossref Google Scholar
43

Koltsova SV, Trushina Y, Haloui M, et al. Ubiquitous [Na+]i/[K+]i-sensitive transcriptome in mammalian cells: evidence for Ca2+i-independent excitation-transcription coupling. PLoS One. 2012;7, e38032.
Crossref Google Scholar
44

Klimanova EA, Sidorenko SV, Smolyaninova LV, et al. Ubiquitous and cell type-specific transcriptomic changes triggered by dissipation of monovalent cation gradients in rodent cells: physiological and pathophysiological implications. Curr Top Membr. 2019;83: 107-150.
Crossref Google Scholar
45

Klimanova EA, Tverskoi AM, Koltsova SV, et al. Time- and dose-dependent actions of cardiotonic steroids on transcriptome and intracellular content of Na+ and K+: a comparative analysis. Sci Rep. 2017;7, e45403.
Crossref Google Scholar
46

Taurin S, Dulin NO, Pchejetski D, et al. c-Fos expression in ouabain-treated vascular smooth muscle cells from rat aorta: evidence for an intracellular-sodium-mediated, calcium-independent mechanism. J Physiol. 2002;543(Pt 3): 835-847.
Crossref Google Scholar
47

Lubin M, Ennis HL. On the role of intracellular potassium in protein synthesis. Biochim Biophys Acta. 1964;80: 614-631.
Crossref Google Scholar
48

Orlov SN, Hamet P. Intracellular monovalent ions as second messengers. J Membr Biol. 2006;210(3): 161-172.
Crossref Google Scholar
49

Orlov SN, Hamet P. Salt and gene expression: evidence for Nai+, Ki+-mediated signaling pathways. Pflueg Arch Eur J Physiol. 2015;467(3): 489-498.
Crossref Google Scholar
50

Cahn F, Lubin M. Inhibition of elongation steps of protein synthesis at reduced potassium concentrations in reticulocytes and reticulocyte lysate. J Biol Chem. 1978;253(21): 7798-7803.
Crossref Google Scholar
51

Tverskoi AM, Sidorenko SV, Klimanova EA, et al. Effects of ouabain on proliferation of human endothelial cells correlate with Na+, K+-ATPase activity and intracellular ratio of Na+ and K+. Biochemistry (Mosc). 2016;81(8): 876-883.
Crossref Google Scholar
52

Das S, Maitra U. Mutational analysis of mammalian translation initiation factor 5 (eIF5): role of interaction between β subunit of eIF2 and eIF5 in eIF5 function in vitro and in vivo. Mol Cell Biol. 2000;20(11): 3942-3950.
Crossref Google Scholar
53

Jennings MD, Pavitt GD. eIF5 is a dual function GAP and GDI for eukaryotic translational control. Small GTPases. 2010;1(2): 118-123.
Crossref Google Scholar
54

Gupta RS, Chora A, Stetsko DK. Cellular basis for the species differences in sensitivity to cardiac glycosides (digitalis). J Cell Physiol. 1986;127(2): 197-206.
Crossref Google Scholar
55

Belusa R, Aizman O, Andersson RM, Aperia A. Changes in Na+-K+-ATPase activity influence cell attachment to fibronectin. Am J Physiol Cell Physiol. 2001;282(2): C302–C309.
Crossref Google Scholar
56

Rajasekaran SA, Hu J, Gopal J, et al. Na, K-ATPase inhibition alters tight junction structure and permeability in human retinal pigment epithelial cells. Am J Physiol Cell Physiol. 2003;284(6): C1497–C1507.
Crossref Google Scholar
57

Rajasekaran SA, Palmer LG, Moon SY, et al. Na, K-ATPase activity is required for formation of tight junctions, desmosomes, and induction of polarity in epithelial cells. Mol Biol Cell. 2001;12(12): 3717-3732.
Crossref Google Scholar
58

Martin PE, Hill NS, Kristensen B, Errington RJ, Griffith TM. Ouabain exerts biphasic effects on connexin functionality and expression in vascular smooth muscle cells. Br J Pharmacol. 2003;140(7): 1261-1271.
Crossref Google Scholar
59

Matchkov VV, Gustafsson H, Rahman A, et al. Interaction between Na+/K+-pump and Na+/Ca2+-exchanger modulates intercellular communication. Circ Res. 2007;100(7): 1026-1035.
Crossref Google Scholar
60

Violette MI, Madan P, Watson AJ. Na+/K+-ATPase regulates tight junction formation and function during mouse preimplantation development. Dev Biol. 2006;289(2): 406-419.
Crossref Google Scholar
61

Lee J-M, Grabb MC, Zipfel GJ, Choi DW. Brain tissue responses to ischemia. J Clin Invest. 2000;106(6): 723-731.
Crossref Google Scholar
62

Rajasekaran AK, Rajasekaran SA. Role of Na-K-ATPase in the assembly of tight junctions. Am J Physiol Ren Physiol. 2003;285(3): F388–F396.
Crossref Google Scholar
63

Gao J, Wymore RS, Wang Y, et al. Isoform-specific stimulation of cardiac Na/K pumps by nanomolar concentrations of glycosides. J Gen Physiol. 2002;119(4): 297-312.
Crossref Google Scholar
64

Li J, Zelenin S, Aperia A, Aizman O. Low doses of ouabain protect from serum deprivation-triggered apoptosis and stimulate kidney cell proliferation via activation of NF-kappaB. J Am Soc Nephrol. 2006;17(7): 1848-1857.
Crossref Google Scholar
65

Ghysel-Burton J, Godfraind T. Stimulation and inhibition of the sodium pump by cardiotonic steroids in relation to their binding sites and ionotropic effect. Br J Pharmacol. 1979;66(2): 175-184.
Crossref Google Scholar
66

Balzan S, D’Urso G, Nicolini G, Forini F, Pellegrino M, Montali U. Erythrocyte sodium pump stimulation by ouabain and an endogenous ouabain-like factor. Cell Biochem Funct. 2007;25(3): 297-303.
Crossref Google Scholar
67

Khundmiri SJ, Metzler MA, Ameen M, Amin V, Rane MJ, Delamere NA. Ouabain induces cell proliferation through calcium dependent phosphorylation of Akt (protein kinase B) in opossum kidney proximal tubule cells. Am J Physiol Cell Physiol. 2006;291(6): C1247–C1257.
Crossref Google Scholar
68

Khundmiri SJ, Salyer SA, Farmer B, et al. Structural determinants for te ouabain-stimulated increase in Na-K ATPase activity. Biochim Biophys Acta. 2014;1843(6): 1089-1102.
Crossref Google Scholar
69

Oselkin M, Tian D, Bergold PJ. Low-dose cardiotonic steroids increase sodium-potassium ATPase activity that protects hippocampal slice cultures from experimental ischemia. Neurosci Lett. 2010;473(2): 67-71.
Crossref Google Scholar
70

Holthouser KA, Mandal A, Merchant ML, et al. Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1 (NHE1)-dependent mechanism in human kidney proximal tubule cells. Am J Physiol Ren Physiol. 2010;299(1): F77–F90.
Crossref Google Scholar
71

Khundmiri SJ. Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules. J Endocrinol. 2014;222(1): R11–R24.
Crossref Google Scholar
72

Askari A. Na+, K+-ATPase: on the number of the ATP sites of the functional unit. J Bioenerg Biomembr. 1987;19(4): 359-374.
Crossref Google Scholar
73

Orlov SN, Klimanova EA, Tverskoi AM, Vladychenskaya EA, Smolyaninova LV, Lopina OD. Nai+, Ki+-dependent and -independent signaling triggered by cardiotonic steroids: facts and artifacts. Molecules. 2017;22(4), e635.
Crossref Google Scholar
74

Aydemir-Koksoy A, Abramowitz J, Allen JC. Ouabain-induced signaling and vascular smooth muscle cell proliferation. J Biol Chem. 2001;276(49): 46605-46611.
Crossref Google Scholar
75

Abramowitz J, Dai C, Hirschi KK, et al. Ouabain- and marinobufagenin-induced proliferation of human umbilical vein smooth muscle cells and a rat vascular smooth muscle cell line, A7r5. Circulation. 2003;108(24): 1049-1054.
Crossref Google Scholar
76

Saunders R, Scheiner-Bobis G. Ouabain stimulates endothelin release and expression in human endothelial cells without inhibiting the sodium pump. Eur J Biochem. 2004;271(5): 1054-1062.
Crossref Google Scholar
77

Nguyen AN, Wallace DP, Blanco G. Ouabain binds with high affinity to the Na+, K+-ATPase in human polycystic kidney cells and induces extracellular signal-regulated kinase activation and cell proliferation. J Am Soc Nephrol. 2007;18(1): 46-57.
Crossref Google Scholar
78

Murata Y, Matsuda T, Tamada K, et al. Ouabain-induced cell proliferation in cultured rat astrocytes. Jpn J Pharmacol. 1996;72(4): 347-353.
Crossref Google Scholar
79

Dmitrieva RI, Doris PA. Ouabain is a potent promoter of growth and activator of ERK1/2 in ouabain-resistant rat renal epithelial cells. J Biol Chem. 2004;278(30): 28160-28166.
Crossref Google Scholar
80

Desfrere L, Karlsson M, Hiyoshi H, et al. Na, K-ATPase signal transduction triggers CREB activation and dendritic growth. Proc Natl Acad Sci USA. 2009;106(7): 2212-2217.
Crossref Google Scholar
81

Segel GB, Lichtman MA. The apparent discrepancy of ouabain inhibition of cation transport and lymphocyte proliferation is explained by time-dependency of ouabain binding. J Cell Physiol. 1980;104(1): 21-26.
Crossref Google Scholar
82

Orlov SN, Hamet P. Apoptosis vs oncosis: role of cell volume and intracellular monovalent cations. Adv Exp Med Biol. 2004;559: 219-233.
Crossref Google Scholar
83

Akimova OA, Platonova AA, Koltsova SV, et al. Cell death triggered by cardiotonic steroids: role of cell volume perturbations and α1-Na+, K+-ATPase subunit. Siberian Med Bull. 2013;12: 24.
Google Scholar
84

Akimova OA, Tverskoi AM, Smolyaninova LV, et al. Critical role of the a1-Na+, K+-ATPase subunit in insensitivity of rodent cells to cytotoxic action of ouabain. Apoptosis. 2015;20(9): 1200-1210.
Crossref Google Scholar
85

Xie Z, Askari A. Na+/K+-ATPase as a signal transducer. Eur J Biochem. 2002;269: 2434-2439.
Crossref Google Scholar
86

Liu J, Xie Z. The sodium pump and cardiotonic steroids-induced signal transduction protein kinases and calcium-signaling microdomains in regulation of transporter trafficking. Biochim Biophys Acta. 2010;1802(12): 1237-1245.
Crossref Google Scholar
87

Haas M, Askari A, Xie Z. Involvement of Src and epidermal growth factor receptor in the signal transducing function of Na+/K+-ATPase. J Biol Chem. 2000;275(36): 27832-27837.
Crossref Google Scholar
88

Haas M, Wang H, Tian J, Xie Z. Src-mediated inter-receptor cross-talk between the Na+, K+-ATPase and epidermal growth factor receptor relays the signal from ouabain to mitogen-activated protein kinases. J Biol Chem. 2002;277(21): 18694-18702.
Crossref Google Scholar
89

Xie J, Ye Q, Cui X, et al. Expression of rat Na-K-ATPase a2 enables ion pumping but not ouabain-induced signaling in a1-deficient porcine renal epithelial cells. Am J Physiol Cell Physiol. 2015;309(6): C373–C382.
Crossref Google Scholar
90

Li Z, Cai T, Tian J, et al. NaKtide, a Na/K-ATPase-derived peptide Src inhibitor, antagonizes ouabain-activated signal transduction in cultured cells. J Biol Chem. 2009;284(31): 21066-21076.
Crossref Google Scholar
91

Tian J, Cai T, Yuan Z, et al. Binding of Src to Na+, K+-ATPase forms a functional signaling complex. Mol Biol Cell. 2006;17: 317-326.
Crossref Google Scholar
92

Gable ME, Abdallah SL, Najjar SM, Liu L, Askari A. Digitalis-induced cell signaling by the sodium pump: on the relation of Src and Na+, K+-ATPase. Biochem Biophys Res Commun. 2014;446(4): 1151-1154.
Crossref Google Scholar
93

Yu H, Cui X, Zhang J, et al. Heterogeneity of signal transduction by Na-K-ATPase α-isoforms: role of SRC interaction. Am J Physiol Cell Physiol. 2018;314(2): C202–C210.
Crossref Google Scholar
94

Liu J, Tian J, Haas M, Shapiro JI, Askari A, Xie Z. Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascade independent of changes in intracellular Na+ and Ca2+ concentrations. J Biol Chem. 2000;275(36): 27838-27844.
Crossref Google Scholar
95

Tian J, Gong X, Xie Z. Signal-transducing function of Na+, K+-ATPase is essential for ouabain’s effect on [Ca2+]i in rat cardiac myocytes. Am J Physiol. 2001;281(5): H1899–H1907.
Crossref Google Scholar
96

Kulikov A, Eva A, Kirch U, Boldyrev A, Scheiner-Bobis G. Ouabain activates signaling pathways associated with cell death in human neuroblastoma. Biochim Biophys Acta. 2007;1768(7): 1691-1702.
Crossref Google Scholar
97

Wu J, Akkuratov EE, Bai Y, Gaskill CM, Askari A, Liu L. Cell signaling associated with Na+/K+-ATPase; activation of phosphatidylinositide 3-kinase IA/Akt by ouabain is independent of Src. Biochem. 2013;52(50): 9059-9067.
Crossref Google Scholar
98

Liu L, Abramowitz J, Askari A, Allen JC. Role of caveolae in ouabain-induced proliferation of cultured vascular smooth muscle cells of the synthetic phenotype. Am J Physiol Heart Circ Physiol. 2004;287(5): H2173–H2182.
Crossref Google Scholar
99

Liu L, Zhao X, Pierre SV, Askari A. Association of PI3K-Akt signaling pathway with digitalis-induced hypertrophy of cardiac myocytes. Am J Physiol Cell Physiol. 2007;293(5): C1489–C1497.
Crossref Google Scholar
100

Aizman O, Uhlen P, Lal M, Brismar H, Aperia A. Ouabain, a steroid hormone that signals with slow calcium oscillations. Proc Natl Acad Sci USA. 2001;98(23): 13420-13424.
Crossref Google Scholar
101

Dolmetsch RE, Xu K, Lewis RS. Calcium oscillations increase the efficiency and specificity of gene expression. Nature. 1998;392(6679): 933-936.
Crossref Google Scholar
102

Lonze BE. Function and regulation of CREB family transcription factors in the nervous system. Neuron. 2002;35(4): 605-623.
Crossref Google Scholar
103

Zhang S, Maimersjo S, Li J, et al. Distinct role of the N-terminal tail of the Na, K-ATPase catalytic subunit as a signal transducer. J Biol Chem. 2006;281(31): 21954-21962.
Crossref Google Scholar
104

Fontana JM, Burlaka I, Khodus G, Brismar H, Aperia A. Calcium oscillations triggered by cardiotonic steroids. FEBS J. 2013;280(21): 5450-5455.
Crossref Google Scholar
105

Somjen GG. Ions in the Brain: Normal Functions, Seizures, and Stroke. New York: Oxford University Press; 2004.
106
Vander AJ. In: Renal Physiology. 5 ed. New York: McGraw-Hill, Inc.; 1991.
107

Rose CR, Konnerth A. NMDA-receptor-mediated Na+ signals in spines and dendrites. J Neurosci. 2001;21(12):4207–4214.
Crossref Google Scholar
108

Fedorova OV, Lakatta EG, Bagrov AY, Melander O. Plasma level of the endogenous sodium pump ligand marinobufagenin is related to the the salt-sensitivity. J Hypertens. 2015;33(3):533–541.
Crossref Google Scholar
109

Schoner W, Scheiner-Bobis G. Role of endogenous cardiotonic steroids in sodium homeostasis. Nephrol Dial Transplant. 2008;23(9):2723–2729.
Crossref Google Scholar
110

Rossi G, Manunta P, Hamlyn JM, et al. Immunoreactive endogenous ouabain in primary aldosteronism and essential hypertension: relationship with plasma renin, aldosterone and blood pressure levels. J Hypertens. 1995;13(10):1181–1191.
Crossref Google Scholar
111

Gottlieb SS, Rogowski AS, Weinberg M, Krichten CM, Hamilton BP, Hamlyn JM. Elevated concentration of endogenous ouabain in patients with congestive heart failure. Circulation. 1992;86(2):420–425.
Crossref Google Scholar
112

van Horck FP, Ahmadian MR, Haeussler LC, Moolenaar WH, Kranenburg O. Characterization of p190RhoCEF, a Rho-specific guanine nucleotide exchange factor that interacts with microtubule. J Biol Chem. 2001;276(7):4948–4956.
Crossref Google Scholar
113

Butt AN, Semra YK, Ho CS, Swaminathan R. Effect of high salt intake on plasma and tissue concentration of endogenous ouabain-like substances in the rat. Life Sci. 1997;61(24):2367–2373.
Crossref Google Scholar
114

Butt AN, Semra YK, Lane SJ, Lee T, Swaminathan R. Endogenous ouabain secretion in man is not regulated by ACTH. J Steroid Biochem Mol Biol. 1998;66(3):151–157.
Crossref Google Scholar
115

Fedorova OV, Anderson DE, Bagrov AY. Plasma marinobufagenin-like and ouabain-like immunoreactivity in adrenocorticotropin-treated rats. Am J Hypertens. 1998;11(7):796–802.
Crossref Google Scholar
116

Gonick HC, Ding Y, Vaziri ND, Bagrov AY, Fedorova OV. Simultaneous measurement of marinobufagenin, ouabain, and hypertension-associated protein in various disease state. Clin Exp Hypertens. 1998;20(5–6):617–627.
Crossref Google Scholar
117

Lopatin DA, Ailmazian EK, Dmitrieva RI, et al. Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia. J Hypertens. 1999;17(8):1179–1187.
Crossref Google Scholar
118

Vakkuri O, Arnason SS, Pouta A, Vuolteenaho O, Leppaluoto J. Radioimmunoassay of plasma ouabain in healthy and pregnant individuals. J Endocrinol. 2000;165(3):669–677.
Crossref Google Scholar
119

Balzan S, Neglia D, Ghione S, et al. Increased circulating level of ouabain-like factor in patients with asymptomatic left ventricular dysfunction. Eur J Heart Fail. 2001;3(2):165–171.
Crossref Google Scholar
120

Fedorova OV, Kolodkin NI, Agalakova NI, Lakatta EG, Bagrov AY. Marinobufagenin, an endogenous α-1 sodium pump ligand, in hypertensive Dahl salt-sensitive rats. Hypertension. 2001;37(2 Pt 2):462–466.
Crossref Google Scholar
121

Fedorova OV, Talan MI, Agalakova NI, Lakatta EG, Bagrov AY. Endogenous ligand of α1 sodium pump, marinobufagenin, is a novel mediator of sodium chloride-dependent hypertension. Circulation. 2002;105(9):1122–1127.
Crossref Google Scholar
122

Fedorova OV, Kolodkin NI, Agalakova NI, et al. Antibody to marinobufagenin lowers blood pressure in pregnant rats on high NaCl intake. J Hypertens. 2005;23(4):835–842.
Crossref Google Scholar
123

Harwood S, Mullen AM, McMahon AC, Dawnay A. Plasma OLS is elevated in mild experimental uremia but is not associated with hypertension. Am J Hypertens. 2001;14(11 Pt 1):1112–1115.
Crossref Google Scholar
124

Berendes E, Cullen P, van Aken H, et al. Endogenous glycosides in critically ill patients. Crit Care Med. 2003;31(5):1331–1337.
Crossref Google Scholar
125

Wang JG, Staessen JA, Messangio E, et al. Salt, endogenous ouabain and blood pressure interactions in general population. J Hypertens. 2003;21(8):1475–1481.
Crossref Google Scholar
126

Balzan S, Nicolini G, Iervasi A, Di Cecco P, Fommei E. Endogenous ouabain and acute salt loading in low-renin hypertension. Am J Hypertens. 2005;18(7):906–909.
Crossref Google Scholar
127

Fridman AI, Matveev SA, Agalakova NI, Fedorova OV, Lakatta EG, Bagrov AY. Marinobufagenin, an endogenous ligand of α-1 Na/K-ATPase, is a marker of congestive heart failure severity. J Hypertens. 2002;20(6):1189–1194.
Crossref Google Scholar
128

Kennedy DJ, Vetteth S, Periyasamy SM, et al. Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy. Hypertension. 2006;47(3):488–495.
Crossref Google Scholar
129

Ferrari P, Torielli L, Ferrandi M, et al. PST2238: a new antihypertensive compound that antagonizes the long-term pressor effect of ouabain. J Pharmacol Exp Therapeut. 1998;285(1):83–94.
Google Scholar
130

Lee K, Jung J, Kim M, Guidotti G. Interaction of the α subunit of Na,K-ATPase with cofilin. Biochem J. 2001;353(Pt 2):377–385.
Crossref Google Scholar
131

Dostanic I, Schultz JEJ, Lorenz JN, Lingrel JB. The α1 isoform of Na,K-ATPase regulates contractility and functionally interacts and co-localizes with the Na/Ca-exchanger in heart. J Biol Chem. 2004;279(52):54053–54061.
Crossref Google Scholar
132

Fedorova OV, Lakatta EG, Bagrov AY. Differential effects of acute NaCl loading on endogenous ouabain-like and marinobufagenin-like ligands of the sodium pump in Dahl hypertensive rats. Circulation. 2000;102:3009–3014.
Crossref Google Scholar
133

Fedorova OV, Talan MI, Agalakova NI, Lakatta EG, Bagrov AY. Coordinated shifts in Na/K-ATPase isoforms and their endogenous ligands during cardiac hypertrophy and failure in NaCl-sensitive hypertension. J Hypertens. 2004;22(2):1–9.
Crossref Google Scholar
134

Dmitrieva RI, Georgiev IY, Shpen VM, Bagrov AY. Bufadienolide nature of an endogenous inhibitor of sodium-potassium adenosine triphosphatase in humans. J Evol Biochem Physiol. 1997;33(3):355–363.
Google Scholar
135

Fedorova OV, Dorofeeva NA, Lopatin DA, Lakatta EG, Bagrov AY. Phorbol diacetate potentiates Na+,K+-ATPase inhibition by a putative endogenous ligand, marinobufagenin. Hypertension. 2002;39(2):298–302.
Crossref Google Scholar
136

Sceinin M, Koulu M, Laurikainen E, Allonen H. Hypokalemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo controlled dose-response study in healthy volunteers. Br J Clin Pharmacol. 1987;24(5):645–653.
Crossref Google Scholar
137

Bagrov AY, Dmitrieva RI, Fedorova OV, Kazakov GP, Roukoyatkina NI, Shpen VM. Endogenous marinobufagenin-like immunoreactive substance: a possible endogenous Na,K-ATPase inhibitor with vasoconstrictor activity. Am J Hypertens. 1996;9(10 Pt 1):982–990.
Crossref Google Scholar
138

Blanco G, Sanchez G, Mercer RW. Comparison of the enzymatic properties of the Na,K-ATPase α3/β1 and α3/β2 isozymes. Biochem. 1995;34(31):9897–9903.
Crossref Google Scholar
139

Brownlee AA, Johnsosn P, Mills IH. Actions of bufalin and cinobufotalin, two bufadienolides respectively more active and less active than ouabain, on ouabain binding and 86Rb uptake by human erythrocytes. Clin Sci. 1990;78(2):169–174.
Crossref Google Scholar
140

Flier JS. Ouabain-like activity in toad skin and its implication for endogenous regulation of ion transport. Nature. 1978;274(5668):285–286.
Crossref Google Scholar
141

Senn N, Lelievre LG, Braquet P, Garay R. High sensitivity of the Na+,K+-pump of human red blood cells to genins of cardiac glycosides. Br J Pharmacol. 1988;93(4):803–810.
Crossref Google Scholar
142

Moller B, Vaag A, Johansen T. Ouabain inhibition of the sodium-potassium pump: estimation of ED50 in different types of human leucocytes in vitro. Br J Clin Pharmacol. 1990;29(1):93–100.
Crossref Google Scholar
143

Tao QF, Hollenberg NK, Price DA, Graves SV. Sodium pump isoform specificity for digitalis-like factor isolated from human peritoneal dialysate. Hypertension. 1996;29(3):815–821.
Crossref Google Scholar
144

Rodriguez-Manas L, Pareja A, Sanchez-Ferrer CF, Casado MA, Salacies MJ. Endothelial role in ouabain-induced contraction of Guinea pig carotid arteries. Hypertension. 1992;20(5):674–681.
Crossref Google Scholar
145

Miakawa-Naito A, Uhlйn P, Lal M, et al. Cell signaling microdomain with Na,K-ATPase and inositol 1,4,5-triphosphate receptor generates calcium oscillations. J Biol Chem. 2003;278(50):50355–50361.
Crossref Google Scholar
146

Peng M, Huang L, Xie Z, Huang W-H, Askari A. Partial inhibition of Na+/K+-ATPase by ouabain induces the Ca2+-dependent expression of early-response genes in cardiac myocytes. J Biol Chem. 1996;271(17):10372–10378.
Crossref Google Scholar
147

Chueh SC, Guh JH, Chen J, Lai MK, Teng CM. Dual effect of ouabain on the regulation of proliferation and apoptosis in human prostatic smooth muscle cells. J Urol. 2001;166(1):347–353.
Crossref Google Scholar
148

Li S, Wattenberg EV. Differential activation of mitogen-activated protein kinases by palytoxin and ouabain, two ligands for the Na+,K+-ATPase. Toxicol Appl Pharmacol. 1998;151(2):377–384.
Crossref Google Scholar
149

Kometiani P, Li J, Gnudi L, Kahn BB, Askari A, Xie Z. Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes: the roles of ras and mitogen-activated protein kinases. J Biol Chem. 1998;273(24):15249–15256.
Crossref Google Scholar
150

Mohammadi K, Liu L, Tian J, Kometiani P, Askari A. Positive ionotropic effect of ouabain on isolated heart is accompanied by activation of signal pathways that link Na+/K+-ATPase to ERK1/2. J Cardiovasc Pharmacol. 2003;41(4):609–614.
Crossref Google Scholar
151

Kometiani P, Liu L, Askari A. Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells. Mol Pharmacol. 2005;67(3):929–936.
Crossref Google Scholar
152

Kotova O, Al-Khalili L, Hooke C, Fedorova OV, Bagrov AY, Chibalin AV. Cardiotonic steroids stimulate glycogen synthesis in human skeletal muscle cells via a Src- and ERK1/2-dependent mechanism. J Biol Chem. 2006;281(29):20085–20094.
Crossref Google Scholar
153

Valente RC, Capella LS, Monteiro RQ, Rumjanek VM, Lopes AG, Capella MAM. Mechanisms of ouabain toxicity. Faseb J. 2003;17(12):1700–1702.
Crossref Google Scholar
Genes & Diseases
Volume 8 Issue 3,
May 2021
Pages 259-271
DOI: 10.1016/j.gendis.2020.01.008
Cite this article:
Orlov SN, Tverskoi AM, Sidorenko SV, et al. Na,K-ATPase as a target for endogenous cardiotonic steroids: What’s the evidence?. Genes & Diseases, 2021, 8(3): 259-271. https://doi.org/10.1016/j.gendis.2020.01.008

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Received: 05 November 2019
Revised: 24 December 2019
Accepted: 09 January 2020
Published: 22 January 2020
© 2020, Chongqing Medical University.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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