NLRP3 inflammasome-modulated angiogenic function of EPC via PI3K/ Akt/mTOR pathway in diabetic myocardial infarction

作者：Jiapeng Li, Qiu Shu, Guang‐Jie Tai, Yiming Liu, Wei Wei, Mengmeng Fu, Pan-Qi Fang, Joseph Nicolao Otieno, Tungalag Battulga, Xiao-Xue Li, Ming Xu · 发表于：Cardiovascular Diabetology · 年份：2025 · DOI：10.1186/s12933-024-02541-3 · 被引用次数：25 · 研究领域：Angiogenesis and VEGF in Cancer、Inflammation biomarkers and pathways、Lipid metabolism and disorders

BACKGROUND: Inflammatory diseases impair the reparative properties of endothelial progenitor cells (EPC); however, the involvement of diabetes in EPC dysfunction associated with myocardial infarction (MI) remains unknown. METHODS: A model was established combining high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice with myocardial infarction. The therapeutic effects of transplanted wild-type EPC, Nlrp3 knockout EPC, and Nlrp3 overexpression EPC were evaluated. Chip and Luciferase assay revealed CEBPB regulated the transcriptional expression of Nlrp3 as a transcription factor in EPC stimulated by high glucose (HG) or advanced glycation end products (AGEs). CO-IP results suggested that USP14 selectively suppressed NLRP3 degradation. KEGG enrichment revealed PI3K/ Akt/mTOR signaling showed striking significance in the entire pathway. RESULTS: In our study, wild-type, Nlrp3 knockout and Nlrp3 overexpressed EPC, intracardiac injections effectively improved cardiac function, increased angiogenesis, and reduced infarct size in mice with myocardial infarction. However, in the HFD/STZ-induced diabetic mice model combined with myocardial infarction, Nlrp3 knockout EPC significantly restored angiogenic capacity. Mechanically, CEBPB regulated the transcriptional level of Nlrp3 as a transcription factor in EPC. Meanwhile, we found that USP14 selectively suppressed NLRP3 protein degradation through the USP motif on the NACHT domain in mediating inflammasome activation. Cardiac f...