Suppressor of IKKÉ is an essential negative regulator of pathological cardiac hypertrophy.

Nat Commun. 2016 Jun 01;7:11432

Ke-Qiong Deng ¹ , Aibing Wang ² , Yan-Xiao Ji ¹ , Xiao-Jing Zhang ¹ , Jing Fang ³ ,

Ke-Qiong Deng ¹ , Aibing Wang ² , Yan-Xiao Ji ¹ , Xiao-Jing Zhang ¹ , Jing Fang ³ , Yan Zhang ¹ , Peng Zhang ¹ , Xi Jiang ¹ , Lu Gao ⁴ , Xue-Yong Zhu ¹ , Yichao Zhao ⁵ , Lingchen Gao ⁵ , Qinglin Yang ⁶ , Xue-Hai Zhu ³ , Xiang Wei ³ , Jun Pu ⁵ , Hongliang Li ¹

+ et al

Author information

¹ Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
² College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China.
³ 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.
⁴ Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
⁵ Department of Cardiology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
⁶ Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294-3360, USA.

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摘要

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 IKKÉ (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.