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Cardiovasc Res. 2007 Jul 15;75(2):408-16. Epub 2007 Mar 30.

Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes.

Author information

1
Cardiology Research Laboratory, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.

Erratum in

  • Cardiovasc Res. 2009 Mar 1;81(4):814.

Abstract

OBJECTIVE:

Neuronal nitric oxide synthase (nNOS) has been shown to regulate intracellular calcium in cardiomyocytes. Calcium in turn modulates extracellular signal-related kinase (ERK) signaling, which is important in tumor necrosis factor-alpha (TNF-alpha) expression during lipopolysaccharide (LPS) stimulation. However, the role of nNOS in LPS-induced TNF-alpha expression is not known. We hypothesized that nNOS suppresses LPS-induced TNF-alpha expression by inhibiting the calcium/ERK signaling pathway.

METHODS AND RESULTS:

Cultured neonatal mouse cardiomyocytes were challenged with LPS for 4 h. While there was no change in the basal Ca(2+) concentration, LPS increased peak Ca(2+) levels. LPS stimulation increased TNF-alpha mRNA and protein levels in wild-type cells however, the responses were enhanced in nNOS(-/-) cardiomyocytes. Treatment with an antisense oligonucleotide against nNOS also significantly enhanced TNF-alpha expression during LPS stimulation. Furthermore, LPS-induced ERK phosphorylation was significantly increased in the nNOS(-/-) compared to wild-type cardiomyocytes. The enhanced TNF-alpha expression in nNOS(-/-) cardiomyocytes was abrogated by an L-type calcium channel blocker verapamil or ERK1 siRNA. Finally, myocardial ERK phosphorylation and TNF-alpha expression were increased while cardiac function was decreased in endotoxemia in nNOS(-/-) compared to wild-type mice.

CONCLUSIONS:

nNOS inhibits LPS-induced TNF-alpha expression in cardiomyocytes and improves cardiac function in endotoxemia. The inhibitory role of nNOS is mediated by a reduction in L-type calcium channel-dependent ERK signaling in cardiomyocytes.

PMID:
17466955
DOI:
10.1016/j.cardiores.2007.03.020
[Indexed for MEDLINE]

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