title: Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor.
abstract: OBJECTIVE
  The purpose of this study was to determine whether p38 mitogen-activated protein kinase (p38-MAPK) contributes to tumor necrosis factor-alpha (TNFalpha)-induced contractile depression.
  
  
  BACKGROUND
  Tumor necrosis factor has both beneficial and detrimental consequences that may result from the activation of different downstream pathways. Tumor necrosis factor activates p38-MAPK, a stress-responsive kinase implicated in contractile depression and cardiac injury.
  
  
  METHODS
  In isolated hearts from mice lacking the p38-MAPK activator, MAPK kinase 3 (MKK3), perfused at constant coronary pressure or flow, we measured the left ventricular developed pressure (LVDP) and the relationship between end-diastolic volume and LVDP in the presence and absence of 10 ng/ml TNFalpha.
  
  
  RESULTS
  Within 15 min at constant pressure, TNFalpha significantly reduced LVDP and coronary flow in outbred and mkk3(+/+) mice. This early negative inotropic effect was associated with a marked phosphorylation of both p38-MAPK and its indirect substrate, HSP27. In hearts lacking MKK3, TNFalpha failed to activate p38-MAPK or to cause significant contractile dysfunction. The actions of TNFalpha were similarly attenuated in MAPK-activated protein kinase 2 (MK2)-deficient hearts, which have a marked reduction in myocardial p38-MAPK protein content, and by the p38-MAPK catalytic site inhibitor SB203580 (1 micromol/l). Under conditions of constant coronary flow, the p38-MAPK activation and contractile depression induced by TNFalpha, though attenuated, remained sensitive to the absence of MKK3 or the presence of SB203580. The role of p38-MAPK in TNFalpha-induced contractile depression was confirmed in isolated murine cardiac myocytes exposed to SB203580 or lacking MKK3.
  
  
  CONCLUSIONS
  Tumor necrosis factor activates p38-MAPK in the intact heart and in isolated cardiac myocytes through MKK3. This activation likely contributes to the early cardiodepressant action of TNFalpha.
authors.affiliation: Cardiovascular Division, King's College London, The Rayne Institute, St. Thomas' Hospital, London, United Kingdom.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bellahcene
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jacquet
authors.forename: Xue B
authors.initials: XB
authors.lastname: Cao
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
authors.forename: Robert S
authors.initials: RS
authors.lastname: Haworth
authors.forename: Joanne
authors.initials: J
authors.lastname: Layland
authors.forename: Alamgir M
authors.initials: AM
authors.lastname: Kabir
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Metin
authors.initials: M
authors.lastname: Avkiran
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marber
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D048371:MAP Kinase Kinase 3 / Q000172:deficiency; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D011494:Protein Kinases / Q000172:deficiency; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines / Q000494:pharmacology; D013318:Stroke Volume / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D048371:MAP Kinase Kinase 3; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C093642:SB 203580