Mesenchymal stem cell-derived extracellular vesicles protect against abdominal aortic aneurysm formation by inhibiting NET-induced ferroptosis
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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
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
참고문헌 (42)
- Sakalihasan, N., "Abdominal aortic aneurysm", Lancet, 365, pp.1577~1589 (2005)
- Golledge, J., "Lack of an effective drug therapy for abdominal aortic aneurysm", J. Intern. Med, 288, pp.6~22 (2020)
- Papayannopoulos, V., "Neutrophil extracellular traps in immunity and disease", Nat. Rev. Immunol, 18, pp.134~147 (2018)
- Meher, A. K., "Novel role of IL(interleukin)-1beta in neutrophil extracellular trap formation and abdominal aortic aneurysms", Arterioscler. Thromb. Vasc. Biol, 38, pp.843~853 (2018)
- Tian, Z., "Gut microbiome dysbiosis contributes to abdominal aortic aneurysm by promoting neutrophil extracellular trap formation", Cell Host Microbe, 30, pp.1450~1463 (2022)
- Spinosa, M., "Resolvin D1 decreases abdominal aortic aneurysm formation by inhibiting NETosis in a mouse model", J. Vasc. Surg, pp.93S~103S (2018)
- Wei, M., "Inhibition of peptidyl arginine deiminase 4-dependent neutrophil extracellular trap formation reduces angiotensin II-induced abdominal aortic aneurysm rupture in mice", Front. Cardiovasc. Med, 8, pp.676612~ (2021)
- Nordon, I. M, "Pathophysiology and epidemiology of abdominal aortic aneurysms", Nat. Rev. Cardiol, 8, pp.92~102 (2011)
- Qiu, Y., "The application of ferroptosis in diseases", Pharmacol. Res, 159, pp.104919~ (2020)
- Chen, Y., "BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection", Pharmacol. Res, 177, pp.106122~ (2022)
- Ren, J., "Key ferroptosis-related genes in abdominal aortic aneurysm formation and rupture as determined by combining bioinformatics techniques", Front. Cardiovasc. Med, 9, pp.875434~ (2022)
- Zhang, H., "Neutrophil extracellular traps mediate m(6)A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells", Int. J. Biol. Sci, 18, pp.3337~3357 (2022)
- Sharma, A. K., "Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment", Circulation, 126, pp.S38~S45 (2012)
- Casado-Diaz, A., "Extracellular vesicles derived from mesenchymal stem cells(MSC)in regenerative medicine : applications in skin wound healing", Front. Bioeng. Biotechnol, 8, pp.146~ (2020)
- Brinkmann, V., "Neutrophil extracellular traps kill bacteria", Science, 303, pp.1532~1535 (2004)
- Yan, H., "Neutrophil proteases promote experimental abdominal aortic aneurysm via extracellular trap release and plasmacytoid dendritic cell activation", Arterioscler. Thromb. Vasc. Biol, 36, pp.1660~1669 (2016)
- Sajeesh, S., "Stem cell derived extracellular vesicles for vascular elastic matrix regenerative repair", Acta Biomater, 113, pp.267~278 (2020)
- Lu, T., "Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia-reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps", Biomaterials, 284, pp.121486~ (2022)
- Chen, H. Z., "Age-associated sirtuin 1 reduction in vascular smooth muscle links vascular senescence and inflammation to abdominal aortic aneurysm", Circ. Res, 119, pp.1076~1088 (2016)
- Chen, X., "Ferroptosis : machinery and regulation", Autophagy, 17, pp.2054~2081 (2021)
- Zhang, X., "Ferroptosis promotes cyst growth in autosomal dominant polycystic kidney disease mouse models", J. Am. Soc. Nephrol, 32, pp.2759~2776 (2021)
- Jiang, X., "Ferroptosis : mechanisms, biology and role in disease", Nat. Rev. Mol. Cell Biol, 22, pp.266~282 (2021)
- Alhussien, M. N., "JAK3 and PI3K mediates the suppressive effects of interferon tau on neutrophil extracellular traps formation during periimplantation period", J. Reprod. Immunol, 145, pp.103321~ (2021)
- Li, B., "Up regulation of isoleucyl-tRNA synthetase promotes vascular smooth muscle cells dysfunction via p38 MAPK", PI3K signaling pathways, 2019, pp.224, 51~57
- Cheng, Q., "Semaphorin 5A suppresses ferroptosis through activation of PI3KAKT-mTOR signaling in rheumatoid arthritis", Cell Death Dis, 13, pp.608~ (2022)
- Ou, Q., "Electrostatic charge-mediated apoptotic vesicle biodistribution attenuates sepsis by switching neutrophil NETosis to apoptosis", Small, 18, pp.e2200306~ (2022)
- Douda, D. N., "Akt is essential to induce NADPH-dependent NETosis and to switch the neutrophil death to apoptosis", Blood, 123, pp.597~600 (2014)
- Delbosc, S., "Porphyromonas gingivalis participates in pathogenesis of human abdominal aortic aneurysm by neutrophil activation. Proof of concept in rats", PLoS ONE, 6, pp.e18679~ (2011)
- Eilenberg, W., "Histone citrullination as a novel biomarker and target to inhibit progression of abdominal aortic aneurysms", Transl. Res, 233, pp.32~46 (2021)
- Eustache, J. H., "Casting a wide net on surgery : the central role of neutrophil extracellular traps", Ann. Surg, 272, pp.277~283 (2020)
- Yang, S., "Neutrophil extracellular traps induce abdominal aortic aneurysm formation by promoting the synthetic and proinflammatory smooth muscle cell phenotype via hippo-YAP pathway", Transl. Res (2022)[DOI]
- Ye, Y., "Repression of the antiporter SLC7A11", glutathione, Kidney Int, pp.2022, 102[DOI]
- Li, N., "Targeting ferroptosis as a novel approach to alleviate aortic dissection", Int. J. Biol. Sci, 18, pp.4118~4134 (2022)
- Zhang, S., "Induction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice", Mol. Med, 28, pp.121~ (2022)
- Yee, P. P., "Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression", Nat. Commun, 11, pp.5424~ (2020)
- Fan, F., "A dual PI3K", HDAC inhibitor induces immunogenic ferroptosis to potentiate cancer immune checkpoint therapy, 2021, pp.81, 6233~6245
- Zhou, H., "The role of phosphoinositide 3-kinases in immune-inflammatory responses : potential therapeutic targets for abdominal aortic aneurysm", Cell Cycle, 21, pp.22~ (2022)
- Zhang, S., "Deficiency of gammadeltaT cells protects against abdominal aortic aneurysms by regulating phosphoinositide 3-kinase", AKT signaling, 2018, pp.67, 899~908
- Pedrazza, L., "Mesenchymal stem cells improves survival in LPS-induced acute lung injury acting through inhibition of NETs formation", J. Cell. Physiol, 232, pp.3552~3564 (2017)
- Navas, A., "Anti-inflammatory and anti-fibrotic effects of human amniotic membrane mesenchymal stem cells and their potential in corneal repair", Stem Cells Transl. Med, 7, pp.906~917 (2018)
- Lin, F., "Mesenchymal stem cells protect against ferroptosis via exosomemediated stabilization of SLC7A11 in acute liver injury", Cell Death Dis, 13, pp.271~ (2022)
- Metzler, K. D., "A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis", Cell Rep, 8, pp.883~896 (2014)
