title: Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy.
abstract: Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways. Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II- or phenylephrine-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli. This interaction between TRAF3 and TBK1 further activated AKT signaling, which ultimately promoted the development of cardiac hypertrophy. Our findings not only reveal a key role of TRAF3 in regulating the hypertrophic response but also uncover TRAF3-TBK1-AKT as a novel signaling pathway in the development of cardiac hypertrophy and heart failure. This pathway may represent a potential therapeutic target for this pathological process.
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).
authors.forename: Ke-Qiong
authors.initials: KQ
authors.lastname: Deng
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).
authors.forename: Guang-Nian
authors.initials: GN
authors.lastname: Zhao
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).
authors.forename: Xueyong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.). lihl@whu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006984:Hypertrophy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D048008:TNF Receptor-Associated Factor 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D048008:TNF Receptor-Associated Factor 3; D000804:Angiotensin II; D010656:Phenylephrine; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: MAP kinase signaling system; TNF receptor-associated factor 3; cardiomegaly