title: TAK1 Regulates Myocardial Response to Pathological Stress via NFAT, NFκB, and Bnip3 Pathways.
abstract: TAK1 (TGFβ-activated kinase-1) signaling is essential in regulating a number of important biological functions, including innate immunity, inflammatory response, cell growth and differentiation, and myocardial homeostasis. The precise role of TAK1 in the adult heart under pathological conditions remains largely unknown. Importantly, we observed that TAK1 is upregulated during compensatory hypertrophy but downregulated in end-stage heart failure. Here we generated transgenic mice with inducible expression of an active TAK1 mutant (TAK1ΔN) in the adult heart. TAK1ΔN transgenic mice developed greater cardiac hypertrophy compared with control mice after transverse aortic constriction (TAC), which was largely blocked by ablation of calcineurin Aβ. Expression of TAK1ΔN also promoted NFAT (nuclear factor of activated T-cells) transcriptional activity in luciferase reporter mice at baseline, which was further enhanced after TAC. Our results revealed that activation of TAK1 promoted adaptive cardiac hypertrophy through a cross-talk between calcineurin-NFAT and IKK-NFκB pathways. More significantly, adult-onset inducible expression of TAK1ΔN protected the myocardium from adverse remodeling and heart failure after myocardial infarction or long-term pressure overload, by preventing cardiac cell death and fibrosis. Mechanistically, TAK1 exerts its cardioprotective effect through activation of NFAT/NFκB, downregulation of Bnip3, and inhibition of cardiac cell death.
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Doan
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Qinghang
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004452:Echocardiography; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D015996:Survival Rate; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D019703:Calcineurin; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D000099151:MAP Kinase Kinase Kinase 7; C508686:BNip3 protein, mouse