Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia |
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Authors: | Ting Zhang Xiangru Lu Jenny Li Peter Chidiac Stephen M Sims Qingping Feng |
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Institution: | (1) Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada;(2) Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada;(3) Lawson Health Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada; |
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Abstract: | Tumor necrosis factor-α (TNF-α) is a major pro-inflammatory cytokine that causes cardiac dysfunction during sepsis. Na/K-ATPase
regulates intracellular Ca2+, which activates mammalian target of rapamycin (mTOR), a regulator of protein synthesis. The aim of this study was to investigate
the role of Na/K-ATPase/mTOR signaling in myocardial TNF-α expression during endotoxemia. Results showed that treatment with
LPS decreased Na/K-ATPase activity in the myocardium in vivo and in cultured neonatal cardiomyocytes. Inhibition of Na/K-ATPase
by ouabain enhanced LPS-induced myocardial TNF-α protein production, but had no effect on TNF-α mRNA expression. More importantly,
ouabain further decreased in vivo cardiac function in endotoxemic mice, which was blocked by etanercept, a TNF-α antagonist.
LPS-induced reduction in Na/K-ATPase activity was prevented by inhibition of PI3K, Rac1 and NADPH oxidase using LY294002,
a dominant-negative Rac1 adenovirus (Ad-Rac1N17) and apocynin, respectively. To assess the role of Rac1 in Ca2+ handling, Ca2+ transients in adult cardiomyocytes from cardiomyocyte-specific Rac1 knockout (Rac1CKO) and wild-type (WT) mice were determined. LPS increased intracellular Ca2+ in WT but not in Rac1CKO cardiomyocytes. Furthermore, LPS rapidly increased mTOR phosphorylation in cardiomyocytes, which was blocked by Rac1N17 and
an inhibitor of calmodulin-dependent protein kinases (CaMKs) KN93, but enhanced by ouabain. Rapamycin, an inhibitor of mTOR
suppressed TNF-α protein levels without any significant effect on its mRNA expression or global protein synthesis. In conclusion,
myocardial Na/K-ATPase activity is inhibited during endotoxemia via PI3K/Rac1/NADPH oxidase activation. Inhibition of Na/K-ATPase
activates Ca2+/CaMK/mTOR signaling, which promotes myocardial TNF-α protein production and cardiac dysfunction during endotoxemia. |
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