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Circulation. 2005 Apr 5;111(13):1637-44. Epub 2005 Mar 28.

Pivotal role of gp91phox-containing NADH oxidase in lipopolysaccharide-induced tumor necrosis factor-alpha expression and myocardial depression.

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Cardiology Research Laboratory, Centre for Critical Illness Research, Lawson Health Research Institute, Department of Medicine, University of Western Ontario, London, Ontario, Canada.



Lipopolysaccharide (LPS) induces cardiomyocyte tumor necrosis factor-alpha (TNF-alpha) production, which is responsible for myocardial depression during sepsis. The aim of this study was to investigate the role of gp91phox-containing NADH oxidase signaling in cardiomyocyte TNF-alpha expression and myocardial dysfunction induced by LPS.


In cultured mouse neonatal cardiomyocytes, LPS increased NADH oxidase (gp91phox subunit) expression and superoxide generation. Deficiency of gp91phox or inhibition of NADH oxidase blocked TNF-alpha expression stimulated by LPS. TNF-alpha induction was also inhibited by tempol, N-acetylcysteine, or 1,3-dimethyl-2-thiourea. NADH oxidase activation by LPS increased ERK1/2 and p38 phosphorylation, and inhibition of ERK1/2 and p38 phosphorylation blocked the effect of NADH oxidase on TNF-alpha expression. Isolated mouse hearts were perfused with LPS (5 microg/mL) alone or in the presence of apocynin for 1 hour. Myocardial TNF-alpha production was decreased in gp91phox-deficient or apocynin-treated hearts compared with those of wild type (P<0.05). To investigate the role of gp91phox-containing NADH oxidase in endotoxemia, mice were treated with LPS (4 mg/kg IP) for 4 and 24 hours, and their heart function was measured with a Langendorff system. Deficiency of gp91phox significantly attenuated LPS-induced myocardial depression (P<0.05).


gp91phox-Containing NADH oxidase is pivotal in LPS-induced TNF-alpha expression and cardiac depression. Effects of NADH oxidase activation are mediated by ERK1/2 and p38 MAPK pathway. The present results suggest that gp91phox-containing NADH oxidase may represent a potential therapeutic target for myocardial dysfunction in sepsis.

[Indexed for MEDLINE]

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