Identification and Experimental Validation of NETosis-Mediated Abdominal Aortic Aneurysm Gene Signature Using Multi-omics, Machine Learning, and Mendelian Randomization.

Journal: Journal of chemical information and modeling
PMID: 40105795

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening disorder with limited therapeutic options. Neutrophil extracellular traps (NETs) are formed by a process known as "NETosis" that has been implicated in AAA pathogenesis, yet the roles and prognostic significance of NET-related genes in AAA remain poorly understood. This study aimed to identify key AAA- and NET-related genes (AAA-NETs-RGs), elucidate their potential mechanisms in contributing to AAA, and explore potential therapeutic compounds for AAA therapy. Through bioinformatics analysis of multiomics and machine learning, we identified six AAA-NETs-RGs: DUSP26, FCN1, MTHFD2, GPRC5C, SEMA4A, and CCR7, which exhibited strong diagnostic potential for predicting AAA progression, were significantly enriched in pathways related to cytokine-cytokine receptor interaction and chemokine signaling. Immune infiltration analysis revealed a causal association between AAA-NETs-RGs and immune cell infiltration. Cell-cell communication analysis indicated that AAA-NETs-RGs predominantly function in smooth muscle cells, B cells, T cells, and NK cells, primarily through cytokine and chemokine signaling. Gene profiling revealed that CCR7 and MTHFD2 exhibited the most significant upregulation in AAA patients compared to non-AAA controls, as well as in AAA models. Notably, genetic depletion of CCR7 and MTHFD2 strongly inhibited Ang II-induced phenotypic switching, functional impairment, and senescence in vascular smooth muscle cells (VSMCs). Based on AAA-NETs-RGs, molecular docking analysis combined with the Connectivity Map (CMap) database identified mirdametinib as a potential therapeutic agent for AAA. Mirdametinib effectively alleviated Ang II-induced phenotypic switching, biological dysfunction, and senescence. These findings provide valuable insights into understanding the pathophysiology of AAA and highlight promising therapeutic strategies targeting AAA-NETs-RGs.

Authors

  • Chengsong Wu
    Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, 710069 Xi'an, Shaanxi, P. R. China.
  • Yuanyuan Ren
    Department of Otolaryngology Head and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, China.
  • Yang Li
    Occupation of Chinese Center for Disease Control and Prevention, Beijing, China.
  • Yue Cui
    National Laboratory of Pattern Recognition and Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Liyao Zhang
    Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, 710069 Xi'an, Shaanxi, P. R. China.
  • Pan Zhang
    College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, People's Republic of China.
  • Xuejiao Zhang
    Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, 710069 Xi'an, Shaanxi, P. R. China.
  • Shangguang Kan
    Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, 710069 Xi'an, Shaanxi, P. R. China.
  • Chan Zhang
    Department of Respiratory Medicine, Xiangya Second Hospital of Central South University, Changsha 410006, Hunan, China.
  • Yuyan Xiong
    Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, 710069 Xi'an, Shaanxi, P. R. China.

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