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Morphine Prevents Ischemia/Reperfusion-Induced Myocardial Mitochondrial Damage by Activating δ-opioid Receptor/EGFR/ROS Pathway

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Abstract

Objective

The purpose of this study was to determine whether the epidermal growth factor receptor (EGFR), which is a classical receptor tyrosine kinase, is involved in the protective effect of morphine against ischemia/reperfusion (I/R)-induced myocardial mitochondrial damage.

Methods

Isolated rats hearts were subjected to global ischemia followed by reperfusion. Cardiac H9c2 cells were exposed to a simulated ischemia solution followed by Tyrode’s solution to induce hypoxia/reoxygenation (H/R) injury. Triphenyltetrazolium chloride (TTC) was used to measure infarct size. The mitochondrial morphological and functional changes were determined using transmission election microscopy (TEM), mitochondrial stress assay, and mitochondrial swelling, respectively. Mitochondrial fluorescence indicator JC-1, DCFH-DA, and Mitosox Red were used to determine mitochondrial membrane potential (△Ψm), intracellular reactive oxygen species (ROS) and mitochondrial superoxide. A TUNUL assay kit was used to detect the level of apoptosis. Western blotting analysis was used to measure the expression of proteins.

Results

Treatment of isolated rat hearts with morphine prevented I/R-induced myocardial mitochondrial injury, which was inhibited by the selective EGFR inhibitor AG1478, suggesting that EGFR is involved in the mitochondrial protective effect of morphine under I/R conditions. In support of this hypothesis, the selective EGFR agonist epidermal growth factor (EGF) reduced mitochondrial morphological and functional damage similarly to morphine. Further study demonstrated that morphine may alleviate I/R-induced cardiac damage by inhibiting autophagy but not apoptosis. Morphine increased protein kinase B (Akt), extracellular regulated protein kinases (ERK) and signal transducer and activator of transcription-3 (STAT-3) phosphorylation, which was inhibited by AG1478, and EGF had similar effects, indicating that morphine may activate Akt, ERK, and STAT-3 via EGFR. Morphine and EGF increased intracellular reactive oxygen species (ROS) generation. This effect of morphine was inhibited by AG1478, indicating that morphine promotes intracellular ROS generation by activating EGFR. However, morphine did not increase ROS generation when cells were transfected with siRNA against EGFR. In addition, EGFR activity was markedly increased by morphine, but the effect of morphine was reversed by naltrindole. These results suggest that morphine may activate EGFR via δ-opioid receptor activation.

Conclusions

Morphine may prevent I/R-induced myocardial mitochondrial damage by activating EGFR through δ-opioid receptors, in turn increasing RISK and SAFE pathway activity via intracellular ROS. Moreover, morphine may reduce myocardial injury by regulating autophagy but not apoptosis.

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Availability of data and material

All data, models, or code generated or used during the study are available from the corresponding author by request.

Code Availability

No code was generated or used during the study.

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Acknowledgments

We gratefully acknowledge Prof. Zhelong Xu from Tianjin Medical University for technical guidance. We thank Springer Nature Author Services for its linguistic assistance during the preparation of this manuscript.

Funding

This work was supported by grant 81700324 from the National Natural Science Foundation of China, grant H2018209378 from the Hebei Provincial Science Foundation of China and grant BJ2018055 from the Hebei Provincial Education Hall Top Talent Project of China.

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Authors and Affiliations

  1. School of Public Health, North China University of Science and Technology, 21 Bohai Avenue, Caofeidian District, Tangshan, 063000, Hebei, China

    Jingman Xu, Yanyi Tian, Xiaodong Li & Wei Tian

  2. Central Laboratory, The Fifth Central Hospital of Tianjin, 300, Tianjin, ,450, China

    Xiyun Bian

  3. Department of Physiology and Pathophysiology, Tianjin Medical University, 300, Tianjin, ,010, China

    Huanhuan Zhao

  4. Department of Neurology, Kailuan Hospital, Tangshan, 063000, Hebei Province, China

    Yujie Sun

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  1. Jingman Xu
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  2. Xiyun Bian
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  3. Huanhuan Zhao
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  4. Yujie Sun
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  5. Yanyi Tian
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  6. Xiaodong Li
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  7. Wei Tian
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Contributions

Wei Tian and Jingman Xu conceived, designed, and carried out the experiments; analyzed the data; and wrote the paper. Xiyun Bian was responsible for taking pictures using TEM and laser scanning confocal microscopy. Huanhuan Zhao performed the experimental model setting and statistical analysis. Yujie Sun and Xiaodong Li helped with cell culture. Yanyi Tian helped with the western blot and apoptosis test.

Corresponding authors

Correspondence to Jingman Xu or Wei Tian.

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The animal experiments were approved by the ethics committee of North China University of Science and Technology (application approval number 2017023). This study conforms to the NIH Guide for the Care and Use of Laboratory Animals (NIH publication No. 85–23, revised 1996).

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Xu, J., Bian, X., Zhao, H. et al. Morphine Prevents Ischemia/Reperfusion-Induced Myocardial Mitochondrial Damage by Activating δ-opioid Receptor/EGFR/ROS Pathway. Cardiovasc Drugs Ther 36, 841–857 (2022). https://doi.org/10.1007/s10557-021-07215-w

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