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TBC1 domain family member 25 protects against myocardial apoptosis and the proinflammatory response triggered by ischemia–reperfusion injury through suppression of the TAK1-JNK/p38 MAPK signaling cascade

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Abstract

TBC1 domain family member 25 (TBC1D25) is a crucial mediator of signal transduction involved in the development of several diseases. Particularly, a cardioprotective role of TBC1D25 has been raised due to its antagonistic action on cardiac hypertrophy. However, whether TBC1D25 protects the myocardium from ischemia–reperfusion injury has not been reported. This work aimed to determine the role of TBC1D25 in myocardial ischemia–reperfusion (MIR) injury and to explore the potential mechanisms involved. Marked decreases in TBC1D25 levels occurred in cardiomyocytes suffering hypoxia/reoxygenation (H/R) injury in vitro and myocardium tissues of rats with MIR injury in vivo. Cardiomyocytes overexpressing TBC1D25 were protected from apoptosis and inflammation triggered by H/R, whereas TBC1D25-deficient cardiomyocytes were more sensitive to H/R injury. Intramyocardial injection of recombinant adenovirus expressing TBC1D25 into rats reduced infarct size and cardiac injury triggered by MIR injury accompanied by decreased myocardial apoptosis and inflammation. A subsequent mechanistic investigation revealed that the signaling cascade of transforming growth factor-β–activated kinase 1 (TAK1)-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) activated under H/R or MIR conditions was markedly restrained by TBC1D25 overexpression. Moreover, TAK1 blockade remarkably reversed the TBC1D25 deficiency–induced aggravating effect on H/R injury. The work concludes that TBC1D25 protects against MIR injury through action on the TAK1-JNK/p38 MAPK signaling cascade. This work suggests TBC1D25 as a potential therapeutic target for MIR injury.

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Data availability

The datasets used during the present study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. The Seventh Department of Cardiovascular Medicine, Xi’an International Medical Center Hospital, Xi’an, 710075, China

    Ziwen Liu

  2. Cardiovascular Care Unit, Xi’an International Medical Center Hospital, Xi’an, 710075, China

    Fujun Shang

  3. The Eighth Department of Cardiovascular Medicine, Xi’an International Medical Center Hospital, No. 777 Xitai Road, Xi’an, 710075, China

    Na Li & Wenting Dong

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  1. Ziwen Liu
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  2. Fujun Shang
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  3. Na Li
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  4. Wenting Dong
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Contributions

ZL designed the work, performed the experiments, and wrote the manuscript. FS and NL performed data analysis and provided technical support. WD contributed to conceptualization and reviewed the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Wenting Dong.

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All animal experiments were approved by the Ethics Committee of Xi’an International Medical Center Hospital.

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The authors declare no competing interests.

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Liu, Z., Shang, F., Li, N. et al. TBC1 domain family member 25 protects against myocardial apoptosis and the proinflammatory response triggered by ischemia–reperfusion injury through suppression of the TAK1-JNK/p38 MAPK signaling cascade. In Vitro Cell.Dev.Biol.-Animal 59, 796–810 (2023). https://doi.org/10.1007/s11626-023-00826-7

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  • DOI: https://doi.org/10.1007/s11626-023-00826-7

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