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Cardiovascular Research Advance Access originally published online on December 12, 2007
Cardiovascular Research 2008 78(1):90-97; doi:10.1093/cvr/cvm100
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Disruption of phospholipase C{gamma}1 signalling attenuates cardiac tumor necrosis factor-{alpha} expression and improves myocardial function during endotoxemia

Tianqing Peng1,2,3,*, E Shen1,2, Jue Fan1, Yan Zhang1, J. Malcolm O. Arnold2,4 and Qingping Feng1,2,4,*

1 Center for Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, 800 Commissioners Road, London, Ontario, Canada N6A 4G5
2 Department of Medicine
3 Department of Pathology
4 Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 4G5

* Corresponding authors. Tel: +1 519 685 8300 Ext. 55441; fax: +1 519 685 8341. E-mail address: tpeng2{at}uwo.ca; qfeng{at}uwo.ca

Aims: Lipopolysaccharide (LPS) induces tumor necrosis factor-{alpha} (TNF-{alpha}) expression in cardiomyocytes, which contributes to myocardial dysfunction during sepsis. The purpose of this study was to investigate the role of phosphatidylinositol (PI) phospholipase C{gamma}1 (PLC{gamma}1) in cardiac TNF-{alpha} expression, and myocardial dysfunction during endotoxemia.

Methods and results: In cultured mouse neonatal cardiomyocytes, LPS increased PLC{gamma}1 phosphorylation. Knockdown of PLC{gamma}1 with specific siRNA or inhibition of PLC{gamma}1 with U73122 [GenBank] attenuated TNF-{alpha} expression induced by LPS. This action of PLC{gamma}1 was mediated through inositol-1,4,5-trisphosphate (IP3)/IP3 receptor (IP3R) pathways since blocking either IP3 or IP3R decreased LPS-induced TNF-{alpha} expression. In contrast, neither diacylglycerol agonist nor antagonist had any evident effect on LPS-induced TNF-{alpha} expression in cardiomyocytes. To investigate the role of PLC{gamma}1 in endotoxemia in vivo, wild-type and heterozygous PLC{gamma}1 knockout (PLC{gamma}1+/–) mice were pre-treated with either U73122 [GenBank] , or its inactive analog U73343 [GenBank] , or vehicle for 15 min, followed by LPS for 4 h. Inhibition of PLC{gamma}1 by U73122 [GenBank] or by heterozygous deletion of the PLC{gamma}1 gene decreased cardiac TNF-{alpha} expression. More importantly, LPS-induced myocardial dysfunction was also attenuated in PLC{gamma}1+/– mice or by U73122 [GenBank] treatment.

Conclusion: PLC{gamma}1 signalling induces cardiac TNF-{alpha} expression and myocardial dysfunction during LPS stimulation. The action of PLC{gamma}1 on TNF-{alpha} expression is mediated through IP3/IP3R pathways. The present results suggest that PLC{gamma}1 may be a potential therapeutic target for myocardial dysfunction in sepsis.

KEYWORDS Sepsis; Cytokine; Cardiomyocytes; Contractility; Phospholipase-C

Time for primary review: 32 days


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