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

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Abstract
Lipopolysaccharide (LPS) induces tumor necrosis factor-α (TNF-α) expression in cardiomyocytes, which contributes to myocardial dysfunction during sepsis. The purpose of this study was to investigate the role of phosphatidylinositol (PI) phospholipase Cγ1 (PLCγ1) in cardiac TNF-α expression, and myocardial dysfunction during endotoxemia. In cultured mouse neonatal cardiomyocytes, LPS increased PLCγ1 phosphorylation. Knockdown of PLCγ1 with specific siRNA or inhibition of PLCγ1 with U73122 attenuated TNF-α expression induced by LPS. This action of PLCγ1 was mediated through inositol-1,4,5-trisphosphate (IP3)/IP3 receptor (IP3R) pathways since blocking either IP3 or IP3R decreased LPS-induced TNF-α expression. In contrast, neither diacylglycerol agonist nor antagonist had any evident effect on LPS-induced TNF-α expression in cardiomyocytes. To investigate the role of PLCγ1 in endotoxemia in vivo, wild-type and heterozygous PLCγ1 knockout (PLCγ1+/−) 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 PLCγ1 by U73122 or by heterozygous deletion of the PLCγ1 gene decreased cardiac TNF-α expression. More importantly, LPS-induced myocardial dysfunction was also attenuated in PLCγ1+/− mice or by U73122 treatment. PLCγ1 signalling induces cardiac TNF-α expression and myocardial dysfunction during LPS stimulation. The action of PLCγ1 on TNF-α expression is mediated through IP3/IP3R pathways. The present results suggest that PLCγ1 may be a potential therapeutic target for myocardial dysfunction in sepsis.

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