Biochimica et biophysica acta. Molecular basis of disease · 2026
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.
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Zheng Wei, Liao Xueyan, Cui Wei, Zhang Ming, Zhao Fengying, Wang Zhiwei, Hu Qionghua
Аннотация
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. 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 in MI development.
METHODS: By establishing an in vitro cardiomyocyte hypoxia-reoxygenation (H/R) model and an in vivo rat model, and combined with flow cytometry, fluorescent probe assay, Western blotting, Hematoxylin-eosin (HE) staining and Masson's trichrome staining, we assessed the effects of VDAC1 silencing on AC16 cardiomyocyte injury, ferroptosis regulation, mitochondrial function, and cardiac function. 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 production and ferroptosis, and alleviated mitochondrial dysfunction. By inhibiting the ubiquitination-dependent degradation pathway of VDAC1, USP11 realized the stable regulation of VDAC1 protein and aggravated the cell damage, ferroptosis, and mitochondrial dysfunction of AC16 cells. YY1 similarly exacerbated these pathological alterations by positively regulating VDAC1 transcription. VDAC1 knockdown with lentivirus intervention improved cardiac function, reduced inflammation, and inhibited ferroptosis in rats.
CONCLUSION: This study demonstrates for the first time that USP11 and YY1 promote the expression of VDAC1 through deubiquitination modification and transcriptional activation, respectively, and mediate the occurrence and development of MIRI, providing potential intervention targets for the clinical treatment of MI.
METHODS: By establishing an in vitro cardiomyocyte hypoxia-reoxygenation (H/R) model and an in vivo rat model, and combined with flow cytometry, fluorescent probe assay, Western blotting, Hematoxylin-eosin (HE) staining and Masson's trichrome staining, we assessed the effects of VDAC1 silencing on AC16 cardiomyocyte injury, ferroptosis regulation, mitochondrial function, and cardiac function. 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 production and ferroptosis, and alleviated mitochondrial dysfunction. By inhibiting the ubiquitination-dependent degradation pathway of VDAC1, USP11 realized the stable regulation of VDAC1 protein and aggravated the cell damage, ferroptosis, and mitochondrial dysfunction of AC16 cells. YY1 similarly exacerbated these pathological alterations by positively regulating VDAC1 transcription. VDAC1 knockdown with lentivirus intervention improved cardiac function, reduced inflammation, and inhibited ferroptosis in rats.
CONCLUSION: This study demonstrates for the first time that USP11 and YY1 promote the expression of VDAC1 through deubiquitination modification and transcriptional activation, respectively, and mediate the occurrence and development of MIRI, providing potential intervention targets for the clinical treatment of MI.