This Article Full Text Full Text (PDF) All Versions of this Article: 111/13/1637    most recent 01.CIR.0000160366.50210.E9v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Peng, T. Articles by Feng, Q. Search for Related Content PubMed PubMed Citation Articles by Peng, T. Articles by Feng, Q. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Cardiomyopathy Related Collections Contractile function Oxidant stress Animal models of human disease Physiological and pathological control of gene expression

(Circulation. 2005;111:1637-1644.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

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

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.

Correspondence to Dr Qingping Feng, London Health Sciences Centre, VRL, 6th Floor, 800 Commissioner Rd, London, Ontario, Canada N6A 4G5. E-mail qfeng{at}uwo.ca

Received July 27, 2004; revision received November 17, 2004; accepted November 19, 2004.

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

This article has been cited by other articles:

				T. Peng, E Shen, J. Fan, Y. Zhang, J. M. O. Arnold, and Q. Feng Disruption of phospholipase C{gamma}1 signalling attenuates cardiac tumor necrosis factor-{alpha} expression and improves myocardial function during endotoxemia Cardiovasc Res, April 1, 2008; 78(1): 90 - 97. [Abstract] [Full Text] [PDF]

				M. Yang, J. Wu, C. M. Martin, P. R. Kvietys, and T. Rui Important role of p38 MAP kinase/NF-{kappa}B signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H994 - H1001. [Abstract] [Full Text] [PDF]

				L. Hammoud, F. Xiang, X. Lu, F. Brunner, K. Leco, and Q. Feng Endothelial nitric oxide synthase promotes neonatal cardiomyocyte proliferation by inhibiting tissue inhibitor of metalloproteinase-3 expression Cardiovasc Res, July 15, 2007; 75(2): 359 - 368. [Abstract] [Full Text] [PDF]

				N. Geoghegan-Morphet, D. Burger, X. Lu, V. Sathish, T. Peng, S. M. Sims, and Q. Feng Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes Cardiovasc Res, July 15, 2007; 75(2): 408 - 416. [Abstract] [Full Text] [PDF]

				C.-C. Yang, M.-C. Ma, C.-T. Chien, M.-S. Wu, W.-K. Sun, and C.-F. Chen Hypoxic preconditioning attenuates lipopolysaccharide-induced oxidative stress in rat kidneys J. Physiol., July 1, 2007; 582(1): 407 - 419. [Abstract] [Full Text] [PDF]

				E. Lepic, D. Burger, X. Lu, W. Song, and Q. Feng Lack of endothelial nitric oxide synthase decreases cardiomyocyte proliferation and delays cardiac maturation Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1240 - C1246. [Abstract] [Full Text] [PDF]

				K. Nakahira, H. P. Kim, X. H. Geng, A. Nakao, X. Wang, N. Murase, P. F. Drain, X. Wang, M. Sasidhar, E. G. Nabel, et al. Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts J. Exp. Med., October 2, 2006; 203(10): 2377 - 2389. [Abstract] [Full Text] [PDF]

				D. Burger, M. Lei, N. Geoghegan-Morphet, X. Lu, A. Xenocostas, and Q. Feng Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase Cardiovasc Res, October 1, 2006; 72(1): 51 - 59. [Abstract] [Full Text] [PDF]