1. Interferon‐regulatory factor‐1 boosts bevacizumab cardiotoxicity by the vascular endothelial growth factor A/14‐3‐3γ axis
- Author
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Xuan‐Ying Chen, Meng‐Qi Xie, Wei‐Lin Huang, Wen‐Juan Li, Yan‐Ni Lv, and Xiao‐Ping Peng
- Subjects
14‐3‐3γ ,Bevacizumab ,Interferon‐regulatory factor‐1 ,Myocardial injury ,VEGFA ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Aim Myocardial injury is a significant cause of death. This study investigated the role and underlying mechanism of interferon‐regulatory factor‐1 (IRF1) in bevacizumab (BVZ)‐induced cardiomyocyte injury. Methods and results HL‐1 cells and C57BL/6 mice receiving BVZ treatment were used to establish in vitro and in vivo models of myocardial injury. The relationship between VEGFA and 14‐3‐3γ was verified through co‐immunoprecipitation and Glutathione S Transferase (GST) pull‐down assay. Cell viability and apoptosis were analysed by MTT, propidium iodide (PI) staining and flow cytometry. The release of lactate dehydrogenase (LDH), cardiac troponins T (cTnT), and creatine kinase MB (CK‐MB) was measured using the enzyme linked immunosorbent assay. The effects of knocking down IRF1 on BVZ‐induced mice were analysed in vivo. IRF1 levels were increased in BVZ‐treated HL‐1 cells. BVZ treatment induced apoptosis, inhibited cell viability, and promoted the release of LDH, cTnT, and CK‐MB. IRF1 silencing suppressed BVZ‐induced myocardial injury, whereas IRF1 overexpression had the opposite effect. IRF1 regulated VEGFA expression by binding to its promoter, with the depletion of VEGFA or 14‐3‐3γ reversing the effects of IRF1 knockdown on the cell viability and apoptosis of BVZ‐treated HL‐1 cells. 14‐3‐3γ overexpression promoted cell proliferation, inhibited apoptosis, and reduced the release of LDH, cTnT, and CK‐MB, thereby alleviating BVZ‐induced HL‐1 cell damage. In vivo, IRF1 silencing alleviated BVZ‐induced cardiomyocyte injury by regulating the VEGFA/14‐3‐3γ axis. Conclusion The IRF1‐mediated VEGFA/14‐3‐3γ signalling pathway promotes BVZ‐induced myocardial injury. Our study provides evidence for potentially new target genes for the treatment of myocardial injury.
- Published
- 2024
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