Published Online
on March 28, 2005

A more recent version of this article appeared on April 5, 2005

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Submitted on July 27, 2004
Revised on November 17, 2004
Accepted on November 19, 2004

Pivotal Role of gp91^phox-Containing NADH Oxidase in Lipopolysaccharide-Induced Tumor Necrosis Factor- Expression and Myocardial Depression

Tianqing Peng MD, MSc, Xiangru Lu MD, and Qingping Feng MD, PhD^*

From the Cardiology Research Laboratory, Centre for Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, Departments of Medicine, Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.

^* To whom correspondence should be addressed. E-mail: qfeng{at}uwo.ca.

Background--Lipopolysaccharide (LPS) induces cardiomyocyte tumor necrosis factor- (TNF-) production, which is responsible for myocardial depression during sepsis. The aim of this study was to investigate the role of gp91^phox-containing NADH oxidase signaling in cardiomyocyte TNF- expression and myocardial dysfunction induced by LPS.

Methods and Results--In cultured mouse neonatal cardiomyocytes, LPS increased NADH oxidase (gp91^phox subunit) expression and superoxide generation. Deficiency of gp91^phox or inhibition of NADH oxidase blocked TNF- expression stimulated by LPS. TNF- 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- expression. Isolated mouse hearts were perfused with LPS (5 µg/mL) alone or in the presence of apocynin for 1 hour. Myocardial TNF- production was decreased in gp91^phox-deficient or apocynin-treated hearts compared with those of wild type (P<0.05). To investigate the role of gp91^phox-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 gp91^phox significantly attenuated LPS-induced myocardial depression (P<0.05).

Conclusions--gp91^phox-Containing NADH oxidase is pivotal in LPS-induced TNF- expression and cardiac depression. Effects of NADH oxidase activation are mediated by ERK1/2 and p38 MAPK pathway. The present results suggest that gp91^phox-containing NADH oxidase may represent a potential therapeutic target for myocardial dysfunction in sepsis.

Key words: lipids • hormones • myocytes • myocardial infarction

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