miR-432 exerts a protective effect against myocardial ischemia/reperfusion injury by activating the β-catenin/HIF-1α pathway and augmenting NRF2-mediated anti-oxidative stress

Rui-Ying Su; Wei-Yan Tai; Hong-Shan Yin; Xiao-Yong Geng

miR-432 exerts a protective effect against myocardial ischemia/reperfusion injury by activating the β-catenin/HIF-1α pathway and augmenting NRF2-mediated anti-oxidative stress

Am J Transl Res. 2023 Jan 15;15(1):392-406. eCollection 2023.

Authors

Rui-Ying Su¹, Wei-Yan Tai², Hong-Shan Yin², Xiao-Yong Geng²

Affiliations

¹ Department of Cardiac Function Inspection, The Third Hospital of Hebei Medical University Shijiazhuang 050051, Hebei, China.
² Department of Cardiology, The Third Hospital of Hebei Medical University Shijiazhuang 050051, Hebei, China.

PMID: 36777848
PMCID: PMC9908467

Abstract

Objective: MicroRNAs (miRNAs) have been shown to play an important role in myocardial ischemia/reperfusion (MI/R) injury. This study aimed to determine the role of miR-432 in MI/R injury.

Methods: We established a MI/R injury model by ligation/untying of the left anterior descending coronary artery, and used viral infection to regulate gene expression, such as that of miR-432 in vitro and in vivo, and used RT-qPCR to detect the expression of the gene at mRNA level. Finally, western blotting and immunochemistry analyses were used to determine the protein level.

Results: The results of this study show that miR-432 is upregulated in the heart following MI/R injury and that miR-432 overexpression showed a significant decrease, while miR-432 knockdown showed a significant increase in the ratio of the infarct area (IA) to the area at risk (AAR) and levels of serum creating phosphokinase (CPK). Moreover, miR-432 augmented the activation of the β-catenin pathway and decreased the rate of apoptosis in the mice heart at 24 hours after MI/R injury by targeting RBM5. At the same time, miR-432 overexpression enhanced HIF-1α activation, while β-catenin deletion attenuated HIF-1α activation induced by miR-432 overexpression. Importantly, β-catenin and HIF-1α knockdown significantly increased the rate of apoptosis and the ratio of IA to AAR and levels of serum CPK induced by miR-432 overexpression at 24 hours after MI/R injury. miR-432 overexpression strongly decreased levels of SOD and GSH-PX activity, and increased levels of MDA activity and the expression of the gp91^phox protein in the mice hearts at 24 hours after MI/R injury, while miR-432 knockdown exerted an opposite effect. miR-432 was also found to have increased NRF2 protein levels by targeting KEAP1 protein expression. NRF2 knockdown reversed the downregulation of the levels of gp91^phox protein and MDA, while it also reversed the upregulation of the levels of SOD and GSH-PX induced by miR-432 overexpression in the heart of the mice at 24 hours after MI/R injury.

Conclusion: miR-432 protects against MI/R injury by activating the β-catenin/HIF-1α pathway and augmenting NRF2-mediated anti-oxidative stress.

Keywords: apoptosis; microRNA; myocardial ischemia/reperfusion injury; oxidative stress.