Lei Li1, Yi Chen1, Jessica Doan1, Jason Murray1, Jeffery D Molkentin1, Qinghang Liu2. 1. 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.). 2. 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.
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. METHODS AND 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.
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. METHODS AND 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-deficientmice. 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.
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