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CD137 Signal Mediates Cardiac Ischemia–Reperfusion Injury by Regulating the Necrosis of Cardiomyocytes

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Abstract

The injury of cardiomyocytes after ischemia–reperfusion is the main reason of cardiac dysfunction. Necrosis is one of the methods of programmed cell death and cardiomyocyte necrosis occurs in the process of reperfusion. The activation of CD137 signal is involved in various diseases. In vivo experiments proved that CD137-/- mice have less heart damage than wild-type mice after ischemia–reperfusion. In vitro experiments, we found that after inhibiting the CD137 signal, the degree of necrosis of HL-1 cells was reduced and it was caused by reducing the Ca2 + overload in the mitochondria, which caused the reduction of mPTP opening. Ca2 + overload in mitochondria induced by activation of CD137 signal was caused by increased Ca2 + released into mitochondria by activation of IP3R and increased MCU level. These results indicate that CD137 signaling aggravates cardiac ischemia–reperfusion injury by inducing myocardial cell necrosis.

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Abbreviations

PCI:

Percutaneous coronary intervention

AMI:

Acute myocardial infarction

ROS:

Reactive oxygen species

mPTP:

Mitochondrial permeability transition pore

VDAC:

Voltage-dependent anion channel

ANT:

Adenine nucleoside translocation protein

CyPD:

Cyclophilin D

TNFRSF:

Tumor necrosis factor receptor superfamily

MAMs:

Mitochondria-associated ER membranes

IP3R:

Inositol-1,4,5-triphosphate receptor

ER:

Endoplasmic reticulum

NCLX:

Mitochondrial sodium–calcium–lithium exchangers

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Acknowledgements

Yao Xu and Chen Shao designed the experiments. Yao Xu, Rui Chen and Guangyao Zang performed these experiments. The work of analyzing the data was completed by Yao Xu and Chen Shao. Yao Xu wrote this article. Chen Shao and Zhongqun Wang revised the article.

Funding

This project was supported by the National Natural Science Foundation of China (81970379), Natural Science Foundation of Jiangsu Province (BK20181227) and Medical Innovation Team Project of Jiangsu Province (CXTDA2017010).

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Authors and Affiliations

  1. Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China

    Yao Xu, Rui Chen, Guangyao Zang, Chen Shao & Zhongqun Wang

  2. Health Science Center, Jiangsu University, Zhenjiang, Jiangsu Province, China

    Jinchuan Yan

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  1. Yao Xu
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Correspondence to Chen Shao or Zhongqun Wang.

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Human Subjects Informed Consent Statement

No human studies were carried out by the authors for this article.

Animal Studies

This study was approved by the Ethics Committee of Jiangsu University and was conducted in accordance with institutional guidelines.

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The authors declare that they have no conflicts of interest.

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Associate Editor Yihua Bei oversaw the review of this article

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Yao Xu and Rui Chen contributed equally to this work and are joint first authors.

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Xu, Y., Chen, R., Yan, J. et al. CD137 Signal Mediates Cardiac Ischemia–Reperfusion Injury by Regulating the Necrosis of Cardiomyocytes. J. of Cardiovasc. Trans. Res. 15, 1163–1175 (2022). https://doi.org/10.1007/s12265-022-10240-1

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