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

by Selleckchem | May 26 2023

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.

Comments：

The study aimed to investigate the role of CD137 signaling in myocardial ischemia-reperfusion (IR) injury, which is associated with NLRP3-mediated inflammatory response. The researchers used genetic ablation to examine the functional significance of CD137 in murine IR model by coronary artery ligation. They also evaluated the expression of CD137 by various methods such as Western-blot, quantitative real-time polymerase chain reaction, and immunohistochemistry. The severity of myocardial IR injury was assessed by Even's blue-TTC staining and echocardiography.

The results showed that CD137 knockout significantly improved cardiac function and reduced NLRP3-mediated inflammatory response and IA/AAR, which were reversed by mitophagy inhibitor Mdivi-1. In vitro experiments with HL-1 cardiomyocytes treated with agonist-CD137 recombinant protein further revealed that activating CD137 signaling inhibited mitophagy and provoked NLRP3-mediated inflammatory response in response to hypoxia/reoxygenation or LPS/ATP. The effects of CD137 signaling could be abolished by either anti-CD137 or mitophagy activator FCCP. The researchers also found that activating CD137 signaling increased mitochondrial ROS by suppressing mitophagy.

In conclusion, the study suggests that activating CD137 signaling aggravates myocardial IR injury by upregulating NLRP3 inflammasome activation through suppressing mitophagy and promoting mtROS generation. The findings of this study provide insights into the underlying mechanisms of myocardial IR injury and may lead to the development of new therapeutic strategies for cardiovascular diseases.