title: Transforming growth factor β-activated kinase 1 signaling pathway critically regulates myocardial survival and remodeling.
abstract: BACKGROUND
  Programmed necrosis (necroptosis) plays an important role in development, tissue homeostasis, and disease pathogenesis. The molecular mechanisms that regulate necroptosis in the heart and its physiological relevance in myocardial remodeling and heart failure remain largely unknown.
  
  
  RESULTS
  Here, we identified an obligate function for TAK1 (transforming growth factor β-activated kinase 1, gene name Map3k7) in regulating necroptotic myocyte death, myocardial remodeling, and heart failure propensity. Cardiac-specific ablation of Map3k7 in mice induced spontaneous apoptosis and necroptosis that led to adverse remodeling and heart failure, and these effects were abolished by ablation of tumor necrosis factor receptor-1. Mechanistically, TAK1 functions as a molecular switch in tumor necrosis factor receptor-1 signaling by regulating the formation of 2 cell death complexes, RIP 1 (receptor-interacting protein 1)-FADD (Fas-associated protein with death domain)-caspase 8 and RIP1-RIP3, a process that is dependent on FADD and caspase 8 as scaffolding molecules. Importantly, inhibition of RIP1 or RIP3 largely blocked necroptotic cell death, adverse remodeling, and heart failure in TAK1-deficient mice.
  
  
  CONCLUSIONS
  These results indicate that TAK1 functions as a key survival factor in the heart by directly antagonizing necroptosis, which is critical for the maintenance of myocardial homeostasis and the prevention of adverse myocardial remodeling.
authors.affiliation: From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (L.L., Y.C., J.D., J.M., Q.L.); and Howard Hughes Medical Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.).
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (L.L., Y.C., J.D., J.M., Q.L.); and Howard Hughes Medical Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (L.L., Y.C., J.D., J.M., Q.L.); and Howard Hughes Medical Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Doan
authors.affiliation: From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (L.L., Y.C., J.D., J.M., Q.L.); and Howard Hughes Medical Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.).
authors.forename: Jason
authors.initials: J
authors.lastname: Murray
authors.affiliation: From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (L.L., Y.C., J.D., J.M., Q.L.); and Howard Hughes Medical Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.).
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (L.L., Y.C., J.D., J.M., Q.L.); and Howard Hughes Medical Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.). qcliu@u.washington.edu jeff.molkentin@cchmc.org.
authors.forename: Qinghang
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053181:Caspase 8 / Q000502:physiology; D002460:Cell Line; D004195:Disease Models, Animal; D053200:Fas-Associated Death Domain Protein / Q000502:physiology; D006333:Heart Failure / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D009336:Necrosis / Q000503:physiopathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D053181:Caspase 8; D053200:Fas-Associated Death Domain Protein; D020930:MAP Kinase Kinase Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7; C505534:Fadd protein, mouse
keywords: apoptosis; heart failure; myocytes, cardiac; necrosis; signal transduction; ventricular remodeling