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Research Article | Open Access

CD137 signaling aggravates myocardial ischemia-reperfusion injury by inhibiting mitophagy mediated NLRP3 inflammasome activation

Guang-Yao ZANG1, Qing YIN1, Chen SHAO1, Zhen SUN1, Li-Li ZHANG1, Yao XU1, Li-Hua LI2, Zhong-Qun WANG1()
Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Abstract

BACKGROUND

The inflammatory response caused by the NLRP3 is closely related to the formation of myocardial ischemia-reperfusion injury. Costimulatory receptor CD137 and its ligand play a crucial role in regulating the inflammatory immune response in atherosclerosis, which is the fundamental cause of cardiovascular diseases. However, the roles of CD137 signaling in the process of myocardial ischaemia-reperfusion (IR) injury remain unknown.

METHODS

Genetic ablation was used to determine the functional significance of CD137 in myocardial IR injury. Expression of CD137 was examined by Western-blot, quantitative real-time polymerase chain reaction, and immunohistochemistry in a murine IR model by coronary artery ligation. Even’s blue-TTC staining and echocardiography to evaluate the severity of myocardial IR injury. Furthermore, HL-1 cardiomyocytes treated with agonist-CD137 recombinant protein were used to explore the underlying mechanism in CD137 signaling-induced NLRP3 inflammasome activation in response to hypoxia/reoxygenation or LPS/ATP.

RESULTS

We demonstrated that CD137 knockout significantly improved cardiac function, accompanied by a markedly reduced NLRP3-mediated inflammatory response and IA/AAR which were reversed by mitophagy inhibitor Mdivi-1. Activating CD137 signaling significantly inhibited mitophagy and provoked NLRP3-mediated inflammatory response in H/R-injured or LPS-primed and ATP-stimulated HL-1 cardiomyocytes, the effects of which could be abolished by either anti-CD137 or mitophagy activator FCCP. Besides, mitochondrial ROS was augmented by activating CD137 signaling through the suppression of mitophagy.

CONCLUSIONS

Our results reveal that activating CD137 signaling aggravates myocardial IR injury by upregulating NLRP3 inflammasome activation via suppressing mitophagy and promoting mtROS generation.

Electronic Supplementary Material

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Journal of Geriatric Cardiology
Volume 20 Issue 3,
March 2023
Pages 223-237
DOI: 10.26599/1671-5411.2023.03.004
Cite this article:
ZANG G-Y, YIN Q, SHAO C, et al. CD137 signaling aggravates myocardial ischemia-reperfusion injury by inhibiting mitophagy mediated NLRP3 inflammasome activation. Journal of Geriatric Cardiology, 2023, 20(3): 223-237. https://doi.org/10.26599/1671-5411.2023.03.004
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