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Войти в исследования Journal of cardiothoracic surgery · 2025
NSUN2 inhibits NCOA4 expression to alleviate ferroptosis and inflammation in sepsis-induced myocardial injury in a m5C manner.
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BoRanyi BaYinchahan, Lv Xinwei, Xiao Dong
Аннотация
BACKGROUND: Sepsis-induced myocardial injury (SIMI) leads to high morbidity and mortality. The 5-methylcytosine (m5C) RNA methyltransferase NOL1/NOP2/SUN domain (NSUN)2 is a therapeutic target for many diseases. The purpose of this study was to investigate the role of NSUN2 in SIMI and the potential mechanism.
METHODS: Both an in vivo cecum ligation and puncture (CLP) SIMI rat model and an in vitro lipopolysaccharide (LPS)-treated H9c2 cardiomyocytes model were established. Reverse transcription (RT)-quantitative polymerase chain reaction (qPCR) was used to detect m5C-related and ferroptosis-related mRNA levels. Enzyme-linked immunosorbent assay was performed to assess inflammatory cytokines levels. Ferroptosis-related indicators were detected by commercial kits and Western blot. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay was performed to detect the m5C level of ferroptosis-related mRNAs. RIP assay was used to explore the interaction between NSUN2 and nuclear receptor coactivator (NCOA)4. The m5C site of NCOA4 was analyzed by dual-luciferase reporter assay.
RESULTS: NSUN2 alleviated LPS-induced SIMI by increasing cell viability and inhibiting inflammation and ferroptosis. In addition, NSUN2 inhibited NCOA4 expression in a m5C-dependent manner. Moreover, overexpressing NCOA4 downregulated cell viability and upregulated LDH activity, inflammation, and ferroptosis in LPS-induced SIMI. In in vivo studies, NSUN2 overexpression reversed CLP-induced myocardial injury, cardiac dysfunction, inflammation, and ferroptosis.
CONCLUSIONS: NSUN2 inhibited NCOA4 expression to alleviate ferroptosis and inflammation in SIMI in a m5C manner, which might provide new information for the clinical treatment of SIMI.
METHODS: Both an in vivo cecum ligation and puncture (CLP) SIMI rat model and an in vitro lipopolysaccharide (LPS)-treated H9c2 cardiomyocytes model were established. Reverse transcription (RT)-quantitative polymerase chain reaction (qPCR) was used to detect m5C-related and ferroptosis-related mRNA levels. Enzyme-linked immunosorbent assay was performed to assess inflammatory cytokines levels. Ferroptosis-related indicators were detected by commercial kits and Western blot. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay was performed to detect the m5C level of ferroptosis-related mRNAs. RIP assay was used to explore the interaction between NSUN2 and nuclear receptor coactivator (NCOA)4. The m5C site of NCOA4 was analyzed by dual-luciferase reporter assay.
RESULTS: NSUN2 alleviated LPS-induced SIMI by increasing cell viability and inhibiting inflammation and ferroptosis. In addition, NSUN2 inhibited NCOA4 expression in a m5C-dependent manner. Moreover, overexpressing NCOA4 downregulated cell viability and upregulated LDH activity, inflammation, and ferroptosis in LPS-induced SIMI. In in vivo studies, NSUN2 overexpression reversed CLP-induced myocardial injury, cardiac dysfunction, inflammation, and ferroptosis.
CONCLUSIONS: NSUN2 inhibited NCOA4 expression to alleviate ferroptosis and inflammation in SIMI in a m5C manner, which might provide new information for the clinical treatment of SIMI.