Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 29, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn336
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JNK1/c-fos inhibits cardiomyocyte TNF-
expression via a negative crosstalk with ERK and p38 MAPK in endotoxemia
1 Departments of Medicine, University of Western Ontario; Centre for Critical Illness Research
2 Departments of Physiology and Pharmacology, University of Western Ontario; Centre for Critical Illness Research
3 Lawson Health Research Institute, London, Ontario, Canada
* Corresponding author: Dr. Qingping Feng, Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada, N6A 5C1. Tel. 519-850-2989; Fax 519-661-4051; E-mail: qfeng{at}uwo.ca
Aims: Myocardial tumor necrosis factor-alpha (TNF-
) production plays an important role in cardiac dysfunction during sepsis. The aim of this study was to investigate the role of c-Jun NH2-terminal kinases (JNK) signalling in cardiomyocyte TNF- expression during lipopolysaccharide (LPS) stimulation and myocardial function in endotoxemic mice.
Methods and Results: In cultured neonatal mouse cardiomyocytes, deficiency of JNK1 or selective inhibition of JNK1 signalling by over-expression of a dominant negative mutant of JNK1 enhanced LPS-induced TNF- expression, which was associated with elevations in phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK). At the organ level, LPS-induced TNF- expression was significantly increased in JNK1–/– compared to wild-type hearts. JNK1 activation by LPS also induced immediate c-fos expression in cardiomyocytes, which was blocked by inhibition of JNK1 signalling. The role of c-fos expression in LPS-induced TNF- expression was investigated in both cultured c-fos–/– cardiomyocytes and isolated c-fos–/– hearts. Deficiency of c-fos significantly enhanced LPS-induced TNF- expression in cardiomyocytes and isolated hearts. Over-expression of c-fos decreased TNF- expression in LPS-stimulated cardiomyocytes, which was associated with a decrease in phosphorylation of ERK1/2 and p38. In mice with endotoxemia, deficiency of either JNK1 or c-fos further decreased cardiac function compared to corresponding wild-type controls.
Conclusions: JNK1/c-fos inhibits ERK1/2 and p38 MAPK signalling, leading to decreased cardiomyocyte TNF- expression and improvements in cardiac function during endotoxemia.
KEYWORDS sepsis; cytokine; signal transduction; cardiomyocytes; cardiac function
Time for primary review: 23 Days
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