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

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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).

CONCLUSIONS:

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.

• Authors: Tianqing Peng, Xiangru Lu, Qingping Feng
• Journal: Circulation (Circulation) Vol. 111 Issue 13 Pg. 1637-44 (Apr 05 2005) ISSN: 1524-4539 [Electronic] United States
• PMID: 15795323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• Membrane Glycoproteins
• Multienzyme Complexes
• Tumor Necrosis Factor-alpha
• NADH oxidase
• NADH, NADPH Oxidoreductases
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Cardiomyopathies (enzymology, etiology)
• Cells, Cultured
• Enzyme Activation
• Gene Expression Regulation
• Heart
• In Vitro Techniques
• Lipopolysaccharides (pharmacology)
• Membrane Glycoproteins (physiology)
• Mice
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Multienzyme Complexes (physiology)
• Myocytes, Cardiac
• NADH, NADPH Oxidoreductases (physiology)
• NADPH Oxidase 2
• NADPH Oxidases (physiology)
• Tumor Necrosis Factor-alpha (genetics)
• p38 Mitogen-Activated Protein Kinases (metabolism)