Abstract
Tax1 banding protein 1 (Tax1bp1) was originally identified as an NF-κB regulatory protein that participated in inflammatory, antiviral and innate immune processes. Tax1bp1 also functions as an autophagy receptor that plays a role in autophagy. Our previous study shows that Tax1bp1 protects against cardiomyopathy in STZ-induced diabetic mice. In this study we investigated the role of Tax1bp1 in heart failure. Pressure overload-induced heart failure model was established in mice by aortic banding (AB) surgery, and angiotensin II (Ang II)-induced heart failure model was established by infusion of Ang II through osmotic minipump for 4 weeks. We showed that the expression levels of Tax1bp1 in the heart were markedly increased 2 and 4 weeks after AB surgery. Knockdown of Tax1bp1 in mouse hearts significantly ameliorated both AB- and Ang II infusion-induced heart failure parameters. On the contrary, AB-induced heart failure was aggravated in cardiac-specific Tax1bp1 transgenic mice. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) under Ang II insult. We demonstrated that the pro-heart failure effect of Tax1bp1 resulted from its interaction with the E3 ligase ITCH to promote the transcription factor P73 ubiquitination and degradation, causing enhanced BCL2 interacting protein 3 (BNIP3)-mediated cardiomyocyte apoptosis. Knockdown ITCH or BNIP3 in NRCMs significantly reduced Ang II-induced apoptosis in vitro. Similarly, BNIP3 knockdown attenuated heart failure in cardiac-specific Tax1bp1 transgenic mice. In the left ventricles of heart failure patients, Tax1bp1 expression level was significantly increased; Tax1bp1 gene expression was negatively correlated with left ventricular ejection fraction in heart failure patients. Collectively, the Tax1bp1 increase in heart failure enhances ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis and induced cardiac injury. Tax1bp1 may serve as a potent therapeutic target for the treatment of heart failure.
• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.
• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.
• Knockout of Tax1bp1 in mouse hearts ameliorated heart failure induced by pressure overload.
• Tax1bp1 interacts with the E3 ligase Itch to promote P73 ubiquitination and degradation, causing enhanced BNIP3-mediated apoptosis.
• Tax1bp1 may become a target of new therapeutic methods for treating heart failure.
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The datasets used and/or analyzed in this study are available from the corresponding author upon reasonable request.
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Funding
This work was supported by grants from the National Natural Science Foundation of China (Nos. 82170382 and 81700353), Hubei Province’s Outstanding Medical Academic Leader Program, National Key R&D Program of China（2018YFC1311300）and the Fundamental Research Funds of the Central Universities (2042017kf0060).
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QQW and QZT: conceived and designed the experiments; YY, QY, TTH, and YW: performed the experiments; QWX and JHZ: analyzed the data; QQW: wrote and revised the manuscript.
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Wu, Qq., Yao, Q., Hu, Tt. et al. Tax1 banding protein 1 exacerbates heart failure in mice by activating ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis. Acta Pharmacol Sin 43, 2562–2572 (2022). https://doi.org/10.1038/s41401-022-00950-2
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DOI: https://doi.org/10.1038/s41401-022-00950-2
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