Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes

doi:10.1016/j.cardiores.2007.03.020

Cardiovascular Research 2007 75(2):408-416; doi:10.1016/j.cardiores.2007.03.020

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Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes

Nicola Geoghegan-Morphet^a^,c^,1, Dylan Burger^a^,c^,1, Xiangru Lu^a, Venkatachalem Sathish^c, Tianqing Peng^b^,d, Stephen M. Sims^c and Qingping Feng^a^,b^,c^,*

^aCardiology Research Laboratory, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada
^bDepartment of Medicine, University of Western Ontario, London, Ontario, Canada
^cDepartment of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
^dDepartment of Pathology, University of Western Ontario, London, Ontario, Canada

^* Corresponding author. Department of Physiology and Pharmacology, University of Western Ontario, Medical Sciences Building, Rm. M254, London, Ontario, Canada N6A 5G1. Tel.: +1 519 850 2989; fax: +1 519 661 4051. qfeng{at}uwo.ca

Objective Neuronal nitric oxide synthase (nNOS) has been shownto regulate intracellular calcium in cardiomyocytes. Calciumin turn modulates extracellular signal-related kinase (ERK)signaling, which is important in tumor necrosis factor-alpha(TNF- ${alpha}$ ) expression during lipopolysaccharide (LPS) stimulation.However, the role of nNOS in LPS-induced TNF- ${alpha}$ expression isnot known. We hypothesized that nNOS suppresses LPS-inducedTNF- ${alpha}$ expression by inhibiting the calcium/ERK signaling pathway.

Methods and results Cultured neonatal mouse cardiomyocytes werechallenged with LPS for 4 h. While there was no changein the basal Ca²⁺ concentration, LPS increased peak Ca²⁺ levels.LPS stimulation increased TNF- ${alpha}$ mRNA and protein levels in wild-typecells however, the responses were enhanced in nNOS^–/–cardiomyocytes. Treatment with an antisense oligonucleotideagainst nNOS also significantly enhanced TNF- ${alpha}$ expression duringLPS stimulation. Furthermore, LPS-induced ERK phosphorylationwas significantly increased in the nNOS^–/– comparedto wild-type cardiomyocytes. The enhanced TNF- ${alpha}$ expression innNOS^–/– cardiomyocytes was abrogated by an L-typecalcium channel blocker verapamil or ERK1 siRNA. Finally, myocardialERK phosphorylation and TNF- ${alpha}$ expression were increased whilecardiac function was decreased in endotoxemia in nNOS^–/–compared to wild-type mice.

Conclusions nNOS inhibits LPS-induced TNF- ${alpha}$ expression in cardiomyocytesand improves cardiac function in endotoxemia. The inhibitoryrole of nNOS is mediated by a reduction in L-type calcium channel-dependentERK signaling in cardiomyocytes.

KEYWORDS Nitric oxide; Nitric oxide synthase; Calcium; TNF- ${alpha}$ ; Signal transduction; Sepsis; Cardiomyocyte

¹ These authors contributed equally to this work.

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