Intracellular Reactive Oxygen Species Mediate the Linkage of Na+/K+-ATPase to Hypertrophy and Its Marker Genes in Cardiac Myocytes

Departments of Pharmacology and Medicine, Medical College of Ohio, Toledo, Ohio 43614, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/1999; 274(27):19323-8. DOI: 10.1074/jbc.274.27.19323
Source: PubMed


We showed before that in cardiac myocytes partial inhibition of Na+/K+-ATPase by nontoxic concentrations of ouabain causes hypertrophy and transcriptional regulations of growth-related marker genes through multiple Ca2+-dependent signal pathways many of which involve Ras and p42/44 mitogen-activated protein kinases. The aim of this work was to explore the roles of intracellular reactive oxygen species (ROS) in these ouabain-initiated pathways. Ouabain caused a rapid generation of ROS within the myocytes that was prevented by preexposure of cells to N-acetylcysteine (NAC) or vitamin E. These antioxidants also blocked or attenuated the following actions of ouabain: inductions of the genes of skeletal alpha-actin and atrial natriuretic factor, repression of the gene of the alpha3-subunit of Na+/K+-ATPase, activation of mitogen-activated protein kinases, activation of Ras-dependent protein synthesis, and activation of transcription factor NF-kappaB. Induction of c-fos and activation of AP-1 by ouabain were not sensitive to NAC. Ouabain-induced inhibition of active Rb+ uptake through Na+/K+-ATPase and the resulting rise in intracellular Ca2+ were also not prevented by NAC. A phorbol ester that also causes myocyte hypertrophy did not increase ROS generation, and its effects on marker genes and protein synthesis were not affected by NAC. We conclude the following: (a) ROS are essential second messengers within some but not all signal pathways that are activated by the effect of ouabain on Na+/K+-ATPase; (b) the ROS-dependent pathways are involved in ouabain-induced hypertrophy; (c) increased ROS generation is not a common response of the myocyte to all hypertrophic stimuli; and (d) it may be possible to dissociate the positive inotropic effect of ouabain from its growth-related effects by alteration of the redox state of the cardiac myocyte.

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    • "In addition to its transporting function, Na C /K C ATPase plays an important role in cell signaling (Xie & Askari 2002). The elegant work from the laboratories of Xie and Askari has elucidated this important role of Na C /K C ATPase that is probably involved in diverse cellular functions and pathophysiological states such as cell growth, hypertrophy, ischemia, development and postnatal maturation of kidneys, and as yet undefined processes (Kometiani et al. 1998, 2005, Xie et al. 1999, Liu et al. 2000, 2007a,b, Aizman et al. 2001, Mohammadi et al. 2001, Aizman & Aperia 2003, Andersson et al. 2004, Li et al. 2006, 2009, 2010, Liang et al. 2006, Tian et al. 2006, 2010, Aperia 2007, 2012, Nguyen et al. 2007, Kennedy et al. 2008, Tian & Xie 2008, Khodus et al. 2011, Brashear et al. 2012, Blanco & Wallace 2013, Burlaka et al. 2013, Fontana et al. 2013, Wu et al. 2013). The laboratory of Zijian Xie made an important discovery by demonstrating that a population of non-ion-transporting and highaffinity Na C /K C ATPase resides in caveolae, forming a signaling complex with Src kinase (Pierre & Xie 2006). "
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