The Na/K-ATPase has a signaling function which appears to be separate from its ion pumping function. This signaling function refers to the transduction of conformational changes in the Na/K-ATPase alpha1 subunit into activating Src’s tyrosine kinase activity, triggering a cascade which generates reactive oxygen species (ROS), modulates other signaling pathways, and causes many physiological and pathophysiological effects. We have recently observed that ROS themselves as well as cardiotonic steroids can actually initiate the signal by directly inducing conformational changes in alpha1. It therefore appears that the Na/K-ATPase signal cascade can serve as a feed forward amplification for ROS with circulating cardiotonic steroids setting the gain. Work in both cellular and animal models of disease suggest that this amplification process is activated in conditions characterized by oxidant stress ranging from cancer to obesity/metabolic syndrome and may serve as a potential clinical target for interventions.
Conflict(s) of Interest
References with DOI
1. Xie JX, Shapiro AP and Shapiro JI. The trade‐off between dietary salt and cardiovascular disease; a role for Na/K‐ATPase signaling? Front Endocrinol (Lausanne). 2014;5:97. https://doi.org/10.3389/fendo.2014.00097
2. Bagrov AY, Shapiro JI and Fedorova OV. Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev. 2009;61:9‐38. https://doi.org/10.1124/pr.108.000711
3. Liu J, Liang M, Liu L, Malhotra D, Xie Z and Shapiro JI. Ouabain‐induced endocytosis of the plasmalemmal Na/K‐ATPase in LLC‐PK1 cells requires caveolin‐1. Kidney Int. 2005;67:1844‐54. https://doi.org/10.1111/j.1523-1755.2005.00283.x
4. Tian J, Liu J, Garlid KD, Shapiro JI and Xie Z. Involvement of mitogen‐activated protein kinases and reactive oxygen species in the inotropic action of ouabain on cardiac myocytes. A potential role for mitochondrial K(ATP) channels. Mol Cell Biochem. 2003;242:181‐7. https://doi.org/10.1007/978-1-4757-4712-6_23
5. Liu J, Tian J, Haas M, Shapiro JI, Askari A and Xie Z. Ouabain interaction with cardiac Na+/K+‐ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. J Biol Chem. 2000;275:27838‐44.
6. Xie Z, Kometiani P, Liu J, Li J, Shapiro JI and Askari A. Intracellular reactive oxygen species mediate the linkage of Na+/K+‐ATPase to hypertrophy and its marker genes in cardiac myocytes. J Biol Chem. 1999;274:19323‐8. https://doi.org/10.1074/jbc.274.27.19323
7. Yan Y, Shapiro AP, Haller S, Katragadda V, Liu L, Tian J, Basrur V, Malhotra D, Xie ZJ, Abraham NG, Shapiro JI and Liu J. Involvement of reactive oxygen species in a feed‐forward mechanism of Na/K‐ATPase‐mediated signaling transduction. J Biol Chem. 2013;288:34249‐58. https://doi.org/10.1074/jbc.m113.461020
8. Kennedy DJ, Chen Y, Huang W, Viterna J, Liu J, Westfall K, Tian J, Bartlett DJ, Tang WH, Xie Z, Shapiro JI and Silverstein RL. CD36 and Na/K ‐ATPase‐alpha1 form a proinflammatory signaling loop in kidney. Hypertension. 2013;61:216‐24. https://doi.org/10.1161/hypertensionaha.112.198770
9.Elkareh J, Kennedy DJ, Yashaswi B, Vetteth S, Shidyak A, Kim EG, Smaili S, Periyasamy SM, Hariri IM, Fedorova L, Liu J, Wu L, Kahaleh MB, Xie Z, Malhotra D, Fedorova OV, Kashkin VA, Bagrov AY and Shapiro JI. Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy. Hypertension. 2007;49:215‐24. https://doi.org/10.1161/01.hyp.0000252409.36927.05
10. Kennedy DJ, Vetteth S, Periyasamy SM, Kanj M, Fedorova L, Khouri S, Kahaleh MB, Xie Z, Malhotra D, Kolodkin NI, Lakatta EG, Fedorova OV, Bagrov AY and Shapiro JI. Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy. Hypertension. 2006;47:488‐95. https://doi.org/10.1161/01.hyp.0000202594.82271.92
11. Haller ST, Kennedy DJ, Shidyak A, Budny GV, Malhotra D, Fedorova OV, Shapiro JI and Bagrov AY. Monoclonal antibody against marinobufagenin reverses cardiac fibrosis in rats with chronic renal failure. Am J Hypertens. 2012;25:690‐6. https://doi.org/10.1038/ajh.2012.17
12. Tian J, Shidyak A, Periyasamy SM, Haller S, Taleb M, El‐Okdi N, Elkareh J, Gupta S, Gohara S, Fedorova OV, Cooper CJ, Xie Z, Malhotra D, Bagrov AY and Shapiro JI. Spironolactone attenuates experimental uremic cardiomyopathy by antagonizing marinobufagenin. Hypertension. 2009;54:1313‐20. https://doi.org/10.1161/hypertensionaha.109.140038
13. Li Z, Zhang Z, Xie JX, Li X, Tian J, Cai T, Cui H, Ding H, Shapiro JI and Xie Z. Na/K‐ATPase mimetic pNaKtide peptide inhibits the growth of human cancer cells. J Biol Chem. 2011;286:32394‐403. https://doi.org/10.1074/jbc.m110.207597
14. Zhang Z, Li Z, Tian J, Jiang W, Wang Y, Zhang X, Li Z, You Q, Shapiro JI, Si S and Xie Z. Identification of hydroxyxanthones as Na/K‐ATPase ligands. Mol Ph armacol. 2010;77:961‐7. https://doi.org/10.1124/mol.110.063974
15. Li Z, Cai T, Tian J, Xie JX, Zhao X, Liu L, Shapiro JI and Xie Z. NaKtide, a Na/K‐ATPase‐derived peptide Src inhibitor, antagonizes ouabain‐activated signal transduction in cultured cells. J Biol Chem. 2009;284:21066‐76. https://doi.org/10.1074/jbc.m109.013821
16. Liang M, Tian J, Liu L, Pierre S, Liu J, Shapiro J and Xie ZJ. Identification of a pool of non‐pumping Na/K‐ATPase. J Biol Chem. 2007;282:10585‐93. https://doi.org/10.1074/jbc.m609181200
17. Sodhi K, Maxwell K, Yan Y, Liu J, Chaudhry MA, Getty M, Xie Z, Abraham NG and Shapiro JI. pNaKtide inhibits Na/K‐ATPase reactive oxygen species amplification and attenuates adipogenesis. SciAdv. 2015;1:e1500781. https://doi.org/10.1126/sciadv.1500781 13 Marshall Journal of Medicine, Vol. 2 , Iss. 2, Art. 4 http://mds.marshall.edu/mjm/vol2/iss2/4 DOI: http://dx.doi.org/10.18590/mjm.2016.vol2.iss2.4
18. Nikitina ER, Mikhailov AV, Nikandrova ES, Frolova EV, Fadeev AV, Shman VV, Shilova VY, Tapilskaya NI, Shapiro JI, Fedorova OV and Bagrov AY. Inpreeclampsia endogenous cardiotonic steroids induce vascular fibrosis and impair relaxation of umbilical arteries. J Hypertens. 2011;29:769‐76 https://doi.org/10.1097/hjh.0b013e32834436a7
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Xie, PhD, Zijian and Shapiro, MD, Joseph I.
"Na/K-ATPase amplification of oxidant stress; a universal but unrecognized clinical target?,"
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