A TAK1 Signaling Pathway Critically Regulates Myocardial Survival and 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 (TGFβ-activated kinase 1, gene name Map3k7) in regulating necroptotic myocyte death, myocardial remodeling, and heart failure propensity. Cardiac-specific ablation of Map3k7 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 (TNFR1). Mechanistically, TAK1 functions as a "molecular switch" in TNFR1 signaling by regulating the formation of two cell death complexes, RIP1-FADD-caspase 8 and RIP1-RIP3, a process that is dependent on FADD and caspase 8 as scaffolding molecules. Importantly, ablation 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.
- Received May 15, 2014.
- Revision received September 16, 2014.
- Accepted September 26, 2014.