TAK1 Activation by NLRP3 Deficiency Confers Cardioprotection Against Pressure Overload-Induced Cardiomyocyte Pyroptosis and Hypertrophy

Xuan Li; Jieyun You; Fangjie Dai; Shijun Wang; Feng Hua Yang; Xingxu Wang; Zhiwen Ding; Jiayuan Huang; Liming Chen; Miyesaier Abudureyimu; Haiyang Tang; Xiangdong Yang; Yaozu Xiang; Peter H Backx; Jun Ren; Junbo Ge; Yunzeng Zou; Jian Wu

doi:10.1016/j.jacbts.2023.05.008

TAK1 Activation by NLRP3 Deficiency Confers Cardioprotection Against Pressure Overload-Induced Cardiomyocyte Pyroptosis and Hypertrophy

JACC Basic Transl Sci. 2023 Aug 9;8(12):1555-1573. doi: 10.1016/j.jacbts.2023.05.008. eCollection 2023 Dec.

Authors

Xuan Li¹, Jieyun You², Fangjie Dai^{1

3}, Shijun Wang¹, Feng Hua Yang⁴, Xingxu Wang², Zhiwen Ding¹, Jiayuan Huang^{1

4}, Liming Chen¹, Miyesaier Abudureyimu⁵, Haiyang Tang^{6

7}, Xiangdong Yang¹, Yaozu Xiang⁸, Peter H Backx^{9

10}, Jun Ren¹, Junbo Ge¹, Yunzeng Zou¹, Jian Wu¹

Affiliations

¹ Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
² Department of Cardiovascular Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
³ Department of Cardiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
⁴ Guangdong Laboratory Animals Monitoring Institute, Guangdong Province Key Laboratory of Laboratory Animals, Guangzhou, China.
⁵ Cardiovascular Department, Shanghai Xuhui Central Hospital, Fudan University, Shanghai, China.
⁶ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou, China.
⁷ Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁸ Shanghai East Hospital, Key Laboratory of Arrhythmias of the Ministry of Education of China, School of Life Sciences and Technology, Tongji University, Shanghai, China.
⁹ Department of Biology, Faculty of Science, York University, Toronto, Ontario, Canada.
¹⁰ Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.

Abstract

A comprehensive view of the role of NLRP3/caspase-1/GSDMD-mediated pyroptosis in pressure overload cardiac hypertrophy is presented in this study. Furthermore, mitigation of NLRP3 deficiency-induced pyroptosis confers cardioprotection against pressure overload through activation of TAK1, whereas this salutary effect is abolished by inhibition of TAK1 activity, highlighting a previously unrecognized reciprocally regulatory role of NLRP3-TAK1 governing inflammation-induced cell death and hypertrophic growth. Translationally, this study advocates strategies based on inflammation-induced cell death might be exploited therapeutically in other inflammatory and mechanical overload disorders, such as myocardial infarction and mitral regurgitation.

Keywords: cardiac remodeling; cell death; hypertrophy; pressure overload; pyroptosis.