Ubiquitin-specific protease 11 and YY1 mediate myocardial ischemia-reperfusion injury in myocardial infarction by regulating the ubiquitination and transcription of voltage-dependent anion channel 1.
Abstract
Background
Myocardial Ischemia-Reperfusion Injury (MIRI) is a key pathological link in the treatment of myocardial infarction (MI), leading to further necrosis of cardiomyocytes and deterioration of cardiac function. The abnormal expression and function of voltage-dependent anion channel 1 (VDAC1) has been confirmed to be closely related to MIRI. This study aims to explore the effects and mechanisms of VDAC1 on MI development.
Methods
By establishing an in vitro cardiomyocyte hypoxia-reoxygenation (H/R) model and an in vivo rat model, and combining techniques including flow cytometry, fluorescent probe assay, Western blotting, Hematoxylin-eosin (HE) staining and Masson's trichrome staining, the effects of VDAC1 silencing on AC16 cardiomyocyte injury, ferroptosis regulation, mitochondrial function, and cardiac function improvement were analyzed. Co-immunoprecipitation (Co-IP) assay, chromatin immunoprecipitation (ChIP) assay, and dual-luciferase reporter assay were used to verify the interactions of ubiquitin-specific protease 11 (USP11) and transcription factor YY1 with VDAC1.
Results
VDAC1 was highly expressed in AC16 under H/R induction. Silencing VDAC1 enhanced cell viability, inhibited cell apoptosis, inflammatory factor expression and ferroptosis, and alleviated mitochondrial dysfunction. By inhibiting the ubiquitination-dependent degradation pathway of VDAC1, USP11 realized the stable regulation of VDAC1 protein and affected the cell damage, ferroptosis, and mitochondrial dysfunction of AC16 cells. YY1 reversed these alterations by positively regulating the transcriptional expression of VDAC1. Intervention with VDAC1 knockdown lentivirus improved cardiac function, reduced inflammation, and inhibited ferroptosis in rats.
Conclusion
This study confirmed for the first time that USP11 and YY1 promoted the expression of VDAC1 through deubiquitination modification and transcriptional activation, respectively, and mediated the occurrence and development of MIRI, providing potential intervention targets for the clinical treatment of MI.