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Article
Rac1 activation induces tumour necrosis factor-α expression and cardiac dysfunction in endotoxemia
Journal of Cellular and Molecular Medicine
  • Ting Zhang, Schulich School of Medicine & Dentistry
  • Xiangru Lu, Schulich School of Medicine & Dentistry
  • Frank Beier, Schulich School of Medicine & Dentistry
  • Qingping Feng, Schulich School of Medicine & Dentistry
Document Type
Article
Publication Date
5-1-2011
URL with Digital Object Identifier
10.1111/j.1582-4934.2010.01095.x
Disciplines
Abstract

Induction of tumour necrosis factor-α (TNF-α) expression leads to myocardial depression during sepsis. However, the underlying molecular mechanisms are not fully understood. The aim of this study was to investigate the role of Rac1 in TNF-α expression and cardiac dysfunction during endotoxemia and to determine the involvement of phosphoinositide-3 kinase (PI3K) in lipopolysaccharide (LPS)-induced Rac1 activation. Our results showed that LPS-induced Rac1 activation and TNF-α expression in cultured neonatal mouse cardiomyocytes. The response was inhibited in Rac1 deficient cardiomyocytes or by a dominant-negative Rac1 (Rac1N17). To determine whether PI3K regulates Rac1 activation, cardiomyocytes were treated with LY294002, a PI3K selective inhibitor. Treatment with LY294002 decreased Rac1 activity as well as TNF-α expression stimulated by LPS. Furthermore, inhibition of PI3K and Rac1 activity decreased LPS-induced superoxide generation which was associated with a significant reduction in ERK1/2 phosphorylation. To investigate the role of Rac1 in myocardial depression during endotoxemiain vivo, wild-type and cardiomyocyte-specific Rac1 deficient mice were treated with LPS (2 mg/kg, i.p.). Deficiency in Rac1 significantly decreased myocardial TNF-α expression and improved cardiac function during endotoxemia. We conclude that PI3K-mediated Rac1 activation is required for induction of TNF-α expression in cardiomyocytes and cardiac dysfunction during endotoxemia. The effect of Rac1 on TNF-α expression seems to be mediated by increased NADPH oxidase activity and ERK1/2 phosphorylation. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Citation Information
Ting Zhang, Xiangru Lu, Frank Beier and Qingping Feng. "Rac1 activation induces tumour necrosis factor-α expression and cardiac dysfunction in endotoxemia" Journal of Cellular and Molecular Medicine Vol. 15 Iss. 5 (2011) p. 1109 - 1121
Available at: http://works.bepress.com/frank-beier/119/