2. Academic Validation
  3. Mesenchymal stem cell-derived extracellular vesicles protect against abdominal aortic aneurysm formation by inhibiting NET-induced ferroptosis

Mesenchymal stem cell-derived extracellular vesicles protect against abdominal aortic aneurysm formation by inhibiting NET-induced ferroptosis

  • Exp Mol Med. 2023 May 1. doi: 10.1038/s12276-023-00986-2.
Liang Chen # 1,  Yuting Liu # 1,  Zheyu Wang # 1,  Leiyang Zhang # 2,  Yi Xu 1,  Yinan Li 1,  Lan Zhang 1,  Guiming Wang 3,  Shuofei Yang 4,  Guanhua Xue 5
Affiliations

Affiliations

  • 1 Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, 200127, Shanghai, China.
  • 2 Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, 210000, Nanjing, China.
  • 3 Department of Vascular Surgery, The First Hospital of Shanxi Medical University, 030001, Taiyuan, China. 13513649533@126.com.
  • 4 Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, 200127, Shanghai, China. doctor_yangshuofei@163.com.
  • 5 Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, 200127, Shanghai, China. guanhuaxue2018@163.com.
  • # Contributed equally.
PMID: 37121969 DOI: 10.1038/s12276-023-00986-2
Abstract

Neutrophil extracellular traps (NETs) play an important role in abdominal aortic aneurysm (AAA) formation; however, the underlying molecular mechanisms remain unclear. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) may exert therapeutic effects on AAA through their immunomodulatory and regenerative abilities. This study aimed to examine the role and mechanism of MSC-EVs in regulating the development of NET-mediated AAA. Excessive release of NETs was observed in patients with AAA, and the levels of NET components were associated with the clinical outcomes of the patients. Datasets from the Gene Expression Omnibus database were analyzed and revealed that the PI3K/Akt pathway and Ferroptosis were strongly associated with NETosis during AAA formation. Further experiments verified that NETs promoted AAA formation by inducing Ferroptosis in smooth muscle cells (SMCs) by inhibiting the PI3K/Akt pathway. The PI3K agonist 740 Y-P, the Ferroptosis inhibitor ferrostatin-1, and Padi4 deficiency significantly prevented AAA formation. MSC-EVs attenuated AAA formation by reducing NET release in an angiotensin II-induced AAA mouse model. In vitro experiments revealed that MSC-EVs reduced the release of NETs by shifting NETosis to Apoptosis. Our study indicates an important role for NET-induced SMC Ferroptosis in AAA formation and provides several potential targets for AAA treatment.

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