Targeting translocator protein protects against myocardial ischemia/reperfusion injury by alleviating mitochondrial dysfunction

Wen,Chenghao; Jiang,Yunfei; Chen,Wen; Xu,Yueyue; Chen,Ganyi; Zhou,Qiang; Liu,Quan; Jiang,Hongwei; Liu,Yafeng; Cao,Xu; Yao,Yiwei; Zhang,Ruoyu; Qiu,Zhibing; Liu,Shengchen

doi:10.3892/etm.2024.12638

Targeting translocator protein protects against myocardial ischemia/reperfusion injury by alleviating mitochondrial dysfunction

Authors:
- Chenghao Wen
- Yunfei Jiang
- Wen Chen
- Yueyue Xu
- Ganyi Chen
- Qiang Zhou
- Quan Liu
- Hongwei Jiang
- Yafeng Liu
- Xu Cao
- Yiwei Yao
- Ruoyu Zhang
- Zhibing Qiu
- Shengchen Liu
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Affiliations: Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China, Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Southeast University, Nanjing, Jiangsu 210006, P.R. China
Published online on: July 4, 2024 https://doi.org/10.3892/etm.2024.12638
Article Number: 349
Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ischemic heart disease (IHD) remains a leading cause of mortalities worldwide, necessitating timely reperfusion to reduce acute mortality. Paradoxically, reperfusion can induce myocardial ischemia/reperfusion (I/R) injury, which is primarily characterized by mitochondrial dysfunction. Translocator protein (TSPO) participates in multiple cellular events; however, its role in IHD, especially in the process of myocardial I/R injury, has not been well determined. The aim of the present study was to investigate the functional role of TSPO in myocardial I/R injury and dissect the concomitant cellular events involved. This study utilized small interfering RNA (siRNA) technology to knock down TSPO expression. The I/R process was simulated using an anoxia/reoxygenation (A/R) model. The role of TSPO in H9c2 cardiomyocytes was assessed using various techniques, such as Western blotting, Flow cytometry, Reverse transcription‑quantitative PCR (RT‑qPCR), Immunofluorescence, Co‑immunoprecipitation (co‑IP) and similar methods. It was found that A/R markedly upregulated the expression of TSPO in cardiomyocytes. Inhibition of TSPO improved myocardial cell apoptosis and damage following A/R stimulation. Additionally, targeting TSPO alleviated mitochondrial damage, reduced mitochondrial ROS release and enhanced ATP synthesis following A/R stimulation. It was further confirmed that A/R stimulation induced a significant increase in the expression of pivotal markers [phosporylated‑PKR‑like ER kinase (PERK)/PERK, activating transcription factor 6 (ATF6) and inositol‑requiring enzyme 1] involved in the adaptive unfolded protein response, which is accompanied by downstream signaling during endoplasmic reticulum (ER) stress. Notably, TSPO knockdown increased the expression of the aforementioned markers and, subsequently, TSPO was confirmed to interact with ATF6, suggesting that TSPO might play a role in ER stress during myocardial I/R injury. Finally, inhibition of TSPO upregulated mitophagy, as indicated by further decreases in P62 and increases in Parkin and PINK1 levels following A/R stimulation. Together, the results suggest that TSPO plays a multifaceted role in myocardial I/R injury. Understanding TSPO‑induced cellular responses could inform targeted therapeutic strategies for patients with IHD.

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