© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Inhibition of p38 MAPK decreases myocardial TNF-alpha expression and improves myocardial function and survival in endotoxemia
aCardiology Research Laboratory, Lawson Health Research Institute, London Health Science Centre, Departments of Medicine, Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 4G5, Canada
bSt. Michael’s Hospital, University of Toronto, Toronto, Ontario M5B 1W8, Canada
qfeng{at}uwo.ca
* Corresponding author. Department of Medicine, London Health Science Centre, 375 South Street, London, Ontario N6A 4G5, Canada. Tel.: +1-519-685-8300x75502; fax: +1-519-667-6545.
Objectives: The role of p38 mitogen-activated protein kinase (MAPK) activation in lipopolysaccharide (LPS)-induced myocardial dysfunction has not been clearly defined. Our aim was to investigate the contribution of p38 MAPK in myocardial tumor necrosis factor-alpha (TNF-
) expression, cardiac function and survival during acute endotoxemia in mice. Methods: Acute endotoxemia was induced by LPS (10 mg/kg, i.p.) in mice. Two hours after LPS treatment, left ventricular (LV) function was assessed. Phosphorylation of p38 MAPK was measured by Western blotting. TNF- mRNA and protein levels were determined by semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Results: LPS rapidly increased phosphorylation of p38 MAPK, followed by TNF- mRNA expression and protein expression in the LV myocardium. Pre-treatment of the p38 MAPK inhibitor SB202190 (2 mg/kg, i.p.) decreased TNF- mRNA and protein by 65 and 36%, respectively (P<0.05). Immunohistochemical staining confirmed that cardiomyocytes were the major source of TNF- production in the myocardium and blocking p38 MAPK activation inhibited TNF- expression in response to LPS. Pre-treatment of SB202190 or a TNF- antagonist etanercept (2 mg/kg, i.p) significantly reversed LPS-induced LV depression (P<0.05). LPS (20 mg/kg, i.p.) induced 94% mortality in mice within 72 h and pre-treatment with SB202190 and etanercept decreased LPS-induced mortality to 65 and 40%, respectively (P<0.01). Conclusion: p38 MAPK activation represents an important mechanism leading to myocardial TNF- production and cardiac dysfunction during acute endotoxemia in mice. Our data suggest that p38 MAPK is a potential therapeutic target of endotoxemia.
KEYWORDS Cytokines; Endotoxins; Protein phosphorylation; Signal transduction; Ventricular function
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  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]
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