Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

Ke-Qiong Deng, Aibing Wang, Yan-Xiao Ji, Xiao-Jing Zhang, Jing Fang, Yan Zhang, Peng Zhang, Xi Jiang, Lu Gao, Xue-Yong Zhu, Yichao Zhao, Lingchen Gao, Qinglin Yang, Xue-Hai Zhu, Xiang Wei, Jun Pu () and Hongliang Li ()
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Ke-Qiong Deng: Renmin Hospital of Wuhan University
Aibing Wang: College of Veterinary Medicine, Hunan Agricultural University
Yan-Xiao Ji: Renmin Hospital of Wuhan University
Xiao-Jing Zhang: Renmin Hospital of Wuhan University
Jing Fang: Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Yan Zhang: Renmin Hospital of Wuhan University
Peng Zhang: Renmin Hospital of Wuhan University
Xi Jiang: Renmin Hospital of Wuhan University
Lu Gao: Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Xue-Yong Zhu: Renmin Hospital of Wuhan University
Yichao Zhao: Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University
Lingchen Gao: Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University
Qinglin Yang: University of Alabama at Birmingham, Birmingham, Alabama 35294-3360, USA
Xue-Hai Zhu: Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Xiang Wei: Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Jun Pu: Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University
Hongliang Li: Renmin Hospital of Wuhan University

Nature Communications, 2016, vol. 7, issue 1, 1-21

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11432

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