Disruption of phospholipase Cγ1 signalling attenuates cardiac tumor necrosis factor-α expression and improves myocardial function during endotoxemia

被引:22
作者
Peng, Tianqing [1 ,2 ,3 ]
Shen, E. [1 ,2 ]
Fan, Jue [1 ]
Zhang, Yan [1 ]
Arnold, J. Malcolm O. [2 ]
Feng, Qingping [1 ,2 ,4 ]
机构
[1] Lawson Hlth Res Inst, Ctr Crit Illness Res, London, ON N6A 4G5, Canada
[2] Univ Western Ontario, Dept Med, London, ON N6A 4G5, Canada
[3] Univ Western Ontario, Dept Pathol, London, ON N6A 4G5, Canada
[4] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 4G5, Canada
基金
加拿大健康研究院;
关键词
sepsis; cytokine; cardiomyocytes; contractility; phospholipase-C;
D O I
10.1093/cvr/cvm100
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 attenuated TNF-alpha expression induced by LPS. This action of PLC gamma 1 was mediated through inositot-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 rote 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, or its inactive analog U73343, or vehicle for 15 min, followed by LPS for 4 h. Inhibition of PLC gamma 1 by U73122 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 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.
引用
收藏
页码:90 / 97
页数:8
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