title: Mitogen-activated protein kinase phosphatase-1 inhibits myocardial TNF-α expression and improves cardiac function during endotoxemia.
abstract: OBJECTIVE
  Myocardial tumour necrosis factor-α (TNF-α) expression induces cardiac dysfunction in endotoxemia. The aim of this study was to investigate the role of mitogen-activated protein kinase phosphatase-1 (MKP1) pathway in myocardial TNF-α expression and cardiac function during endotoxemia.
  
  
  RESULTS
  Lipopolysaccharide (LPS) increased MKP1 expression in the myocardium in vivo and in cultured neonatal cardiomyocytes in vitro. LPS-induced extracellular signal-regulated kinase (ERK) 1/2 and p38 phosphorylation in the myocardium was prolonged in MKP1(-/-) mice. Myocardial TNF-α mRNA and protein levels were enhanced in MKP1(-/-) compared with wild-type (WT) mice in endotoxemia, leading to a further decrease in cardiac function. To study if Rac1/p21-activated kinase 1 (PAK1) signalling regulates MKP1 expression, cardiomyocytes were treated with LPS. Inhibition of Rac1 and PAK1 by a dominant negative Rac1 adenovirus (Ad-Rac1N17) and PAK1 siRNA, respectively, blocked LPS-induced MKP1 expression in cardiomyocytes. PAK1 siRNA also decreased p38 and c-Jun N-terminal kinase (JNK) activation, and TNF-α expression induced by LPS. Furthermore, deficiency in either Rac1 or JNK1 decreased myocardial MKP1 expression in endotoxemic mice.
  
  
  CONCLUSIONS
  LPS activates the Rac1/PAK1 pathway, which increases myocardial MKP1 expression via JNK1. MKP1 attenuates ERK1/2 and p38 activation, inhibits myocardial TNF-α expression, and improves cardiac function in endotoxemia. Thus, MKP1 represents an important negative feedback mechanism limiting pro-inflammatory response in the heart during sepsis.
authors.affiliation: Department of Physiology and Pharmacology,  Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario,  Canada N6A 5C1.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.forename: Paul
authors.initials: P
authors.lastname: Arnold
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Reshma
authors.initials: R
authors.lastname: Baliga
authors.forename: Hong
authors.initials: H
authors.lastname: Huang
authors.forename: John Anthony
authors.initials: JA
authors.lastname: Bauer
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000818:Animals; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D019446:Endotoxemia / Q000378:metabolism* / Q000503:physiopathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D008070:Lipopolysaccharides; D009479:Neuropeptides; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein