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

Background: Inflammation was only recently appreciated in pressure overload-induced cardiac remodeling, while the underlying orchestration of inflammatory cell death and hypertrophic growth is largely unknown. Objective: This study sought to unveil a pivotal role for transforming growth factor β-activated kinase 1 (TAK1) in the coordination of Nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3)/Caspase-1/Gasdermin D (GSDMD)-mediated pyroptosis (inflammatory cell death) and hypertrophic growth under pressure overload. Methods and Results: NLRP3-knockout mice and MCC950 (NLRP3 inhibitor)-treated neonatal mouse ventricular myocytes with overexpression of Caspase-1 or GSDMD, or knockdown of TAK1, were subjected to transverse aortic constriction or angiotensin II to investigate the effect of NLRP3-TAK1 interaction in myocardial hypertrophy. Our data indicated that NLRP3 deficiency attenuated myocardial pyroptosis and preserved cardiac function under pressure overload, while the cardioprotection was abolished by direct (GSDMD) or indirect (Caspase-1) enhancement of pyroptosis. Unexpectedly, NLRP3 deficiency activated TAK1 in response to pressure overload, while cardiac-specific TAK1 knockdown exacerbated cardiac remodeling in both wild-type and NLRP3-knockout mice, accompanied with aggravated pyroptosis, suggesting a regulatory role of NLRP3-TAK1 in cardiomyocyte pyroptosis and hypertrophy. Conclusions: The NLRP3 deficiency-induced pyroptotic mitigation confers cardioprotection against pressure overload by activation of TAK1, while this salutary effect is abolished by inhibition of TAK1 activity, highlighting a previously unrecognized regulation governing pyroptosis and hypertrophy by linking NLRP3 and TAK1.Funding Information: This work was supported by the National Natural Science Foundation of China (81941002, 82170389, 82170255, 81730009, 81770274, 81670228, and 81500191), Laboratory Animal Science Foundation of Science and Technology Commission of Shanghai Municipality (201409004300, 21140904400), Health Science and Technology Project of Shanghai Pudong New Area Health Commission (PW2019A- 13), and "Rising Sun" Excellent Young Medical Talents Program of Shanghai East Hospital (2019xrrcjh03).Conflict of Interests: None.Ethical Approval: The animal experiments were approved by the Animal Care and Use Committee of Zhongshan Hospital, Fudan University and procedures were performed in accordance with National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 2011).