title: Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy.
abstract: Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.|Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Ke-Qiong
authors.initials: KQ
authors.lastname: Deng
authors.affiliation: College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China.
authors.forename: Aibing
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.|Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Yan-Xiao
authors.initials: YX
authors.lastname: Ji
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.|Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.|Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.|Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.|Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.|Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Xue-Yong
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
authors.forename: Lingchen
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294-3360, USA.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Xue-Hai
authors.initials: XH
authors.lastname: Zhu
authors.affiliation: Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Cardiology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Pu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.|Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C506822:SIKE protein, mouse; C583271:SIKE1 protein, human; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases