HIF-1α-regulated lncRNA-TUG1 promotes mitochondrial dysfunction and pyroptosis by directly binding to FUS in myocardial infarction

• DOI: 10.1038/s41420-022-00969-8
• Publication Date: 2022-04-08T06:10:28Z
• Authors: Yong-Wang Wang; Hong-Zhi Dong; Yong-Xing Tan; Xu Bao; Ying-Man Su; Xin Li; Fang Jiang; Jing Liang; Zhen-Cai Huang; Yan-Ling Ren; Yu-Li Xu; Qiang Su
• Keywords: Pyroptosis; Terminal deoxynucleotidyl transferase; Creatine kinase

Myocardial infarction (MI) is a fatal heart disease that affects millions of lives worldwide each year. This study investigated the roles HIF-1α/lncRNA-TUG1 in mitochondrial dysfunction and pyroptosis MI. CCK-8, DHE, lactate dehydrogenase (LDH) assays, JC-1 staining were performed to measure proliferation, reactive oxygen species (ROS), LDH leakage, damage hypoxia/reoxygenation (H/R)-treated cardiomyocytes. Enzyme-linked immunoassay (ELISA) flow cytometry used detect LDH, creatine kinase (CK), its isoenzyme (CK-MB) levels caspase-1 activity. Chromatin immunoprecipitation (ChIP), luciferase assay, RNA-immunoprecipitation (RIP) assess interaction between HIF-1α, TUG1, FUS. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, immunohistochemistry TUG1 pyroptosis-related molecules. Hematoxylin eosin (HE), 2,3,5-triphenyltetrazolium chloride (TTC), terminal deoxynucleotidyl transferase dUTP risk end labelling (TUNEL) employed examine morphology, area, myocardial injury MI mouse model. Mitochondrial induced H/R-treated cardiomyocytes, accompanied by an increase expression HIF-α TUG1. HIF-1α promoted directly binding promoter. silencing inhibited H/R-induced ROS production, proteins NLRP3, GSDMD. Additionally, H/R elevated FUS which silencing. Fused sarcoma (FUS) overexpression reversed effect on activation. However, inhibitor N-acetylcysteine (NAC) protective knockdown cardiomyocyte damage. The vivo model showed increased infarction, injury, pyroptosis, targeting upregulated promotes combining with FUS, thereby promoting occurrence HIF-1α/TUG1/FUS may serve as potential treatment target for