Gene interactions and pathways from curated databases and text-mining
Basic Res Cardiol 2012, PMID: 22351078

Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia.

Zhang, Ting; Lu, Xiangru; Li, Jenny; Chidiac, Peter; Sims, Stephen M; Feng, Qingping

Tumor necrosis factor-α (TNF-α) is a major pro-inflammatory cytokine that causes cardiac dysfunction during sepsis. Na/K-ATPase regulates intracellular Ca(2+), 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 Ca(2+) handling, Ca(2+) transients in adult cardiomyocytes from cardiomyocyte-specific Rac1 knockout (Rac1(CKO)) and wild-type (WT) mice were determined. LPS increased intracellular Ca(2+) in WT but not in Rac1(CKO) 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 Ca(2+)/CaMK/mTOR signaling, which promotes myocardial TNF-α protein production and cardiac dysfunction during endotoxemia.

Diseases/Pathways annotated by Medline MESH: Calcium Signaling, Endotoxemia
Document information provided by NCBI PubMed

Text Mining Data

tumor necrosis factor-alpha ⊣ Na/K-ATPase: " Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia "

TNF-a ⊣ Na/K-ATPase/mTOR signaling: " The aim of this study was to investigate the role of Na/K-ATPase/mTOR signaling in myocardial TNF-a expression during endotoxemia "

TNF-a ⊣ Na/K-ATPase/mTOR: " The aim of this study was to investigate the role of Na/K-ATPase/mTOR signaling in myocardial TNF-a expression during endotoxemia "

TNF-a → LPS: " Inhibition of Na/K-ATPase by ouabain enhanced LPS induced myocardial TNF-a protein production, but had no effect on TNF-a mRNA expression "

Na/K-ATPase ⊣ NADPH oxidase: " 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 "

Na/K-ATPase ⊣ LPS: " 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 "

Na/K-ATPase ⊣ PI3K: " 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 "

Na/K-ATPase ⊣ Rac1: " 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 "

mTOR → LPS: " 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 "

/CaMK/mTOR ⊣ Na/K-ATPase: " Inhibition of Na/K-ATPase activates Ca ( 2+ ) /CaMK/mTOR signaling, which promotes myocardial TNF-a protein production and cardiac dysfunction during endotoxemia "

/CaMK/mTOR signaling ⊣ Na/K-ATPase: " Inhibition of Na/K-ATPase activates Ca ( 2+ ) /CaMK/mTOR signaling , which promotes myocardial TNF-a protein production and cardiac dysfunction during endotoxemia "

Manually curated Databases

No curated data.