title: Unrestrained p38 MAPK activation in Dusp1/4 double-null mice induces cardiomyopathy.
abstract: BACKGROUND
  Mitogen-activated protein kinases (MAPKs) are activated in the heart by disease-inducing and stress-inducing stimuli, where they participate in hypertrophy, remodeling, contractility, and heart failure. A family of dual-specificity phosphatases (DUSPs) directly inactivates each of the MAPK terminal effectors, potentially serving a cardioprotective role.
  
  
  OBJECTIVE
  To determine the role of DUSP1 and DUSP4 in regulating p38 MAPK function in the heart and the effect on disease.
  
  
  RESULTS
  Here, we generated mice and mouse embryonic fibroblasts lacking both Dusp1 and Dusp4 genes. Although single nulls showed no molecular effects, combined disruption of Dusp1/4 promoted unrestrained p38 MAPK activity in both mouse embryonic fibroblasts and the heart, with no change in the phosphorylation of c-Jun N-terminal kinases or extracellular signal-regulated kinases at baseline or with stress stimulation. Single disruption of either Dusp1 or Dusp4 did not result in cardiac pathology, although Dusp1/4 double-null mice exhibited cardiomyopathy and increased mortality with aging. Pharmacological inhibition of p38 MAPK with SB731445 ameliorated cardiomyopathy in Dusp1/4 double-null mice, indicating that DUSP1/4 function primarily through p38 MAPK in affecting disease. At the cellular level, unrestrained p38 MAPK activity diminished cardiac contractility and Ca2+ handling, which was acutely reversed with a p38 inhibitory compound. Poor function in Dusp1/4 double-null mice also was partially rescued by phospholamban deletion.
  
  
  CONCLUSIONS
  Our data demonstrate that Dusp1 and Dusp4 are cardioprotective genes that play a critical role in the heart by dampening p38 MAPK signaling that would otherwise reduce contractility and induce cardiomyopathy.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Mannix
authors.initials: M
authors.lastname: Auger-Messier
authors.forename: Federica
authors.initials: F
authors.lastname: Accornero
authors.forename: Sanjeewa A
authors.initials: SA
authors.lastname: Goonasekera
authors.forename: Orlando F
authors.initials: OF
authors.lastname: Bueno
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Jop H
authors.initials: JH
authors.lastname: van Berlo
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics; D009202:Cardiomyopathies / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency* / Q000235:genetics; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology; D005786:Gene Expression Regulation; D006439:Hemodynamics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D054638:Dual Specificity Phosphatase 1; D047428:Protein Kinase Inhibitors; D017027:Protein Tyrosine Phosphatases; D048051:p38 Mitogen-Activated Protein Kinases; D000099211:Phospholamban; C517020:Dusp1 protein, mouse; C522186:Dusp4 protein, mouse