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Dexmedetomidine Alleviates Abdominal Aortic Aneurysm by Activating Autophagy Via AMPK/mTOR Pathway

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Abstract

Background

Abdominal aortic aneurysms (AAA) are a critical global health issue with increasing prevalence. Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist that has previously been shown to play a protective role in AAA. Nevertheless, the mechanisms underlying its protection effect remain not fully understood.

Methods

A rat AAA model was established via intra-aortic porcine pancreatic elastase perfusion with or without DEX administration. The abdominal aortic diameters of rats were measured. Hematoxylin-eosin and Elastica van Gieson staining were conducted for histopathological observation. TUNEL and immunofluorescence staining were utilized to detect cell apoptosis and α-SMA/LC3 expression in the abdominal aortas. Protein levels were determined using western blotting.

Results

DEX administration repressed the dilation of aortas, alleviated pathological damage and cell apoptosis, and suppressed phenotype switching of vascular smooth muscle cells (VSMCs). Moreover, DEX activated autophagy and regulated the AMP-activated protein kinase/mammalian target of the rapamycin (AMPK/mTOR) signaling pathway in AAA rats. Administration of the AMPK inhibitor attenuated the DEX-mediated ameliorative effects on AAA in rats.

Conclusion

DEX ameliorates AAA in rat models by activating autophagy via the AMPK/mTOR pathway.

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Data availability

The datasets used during the current study are available from the corresponding author on reasonable request.

References

  1. Stepien KL, Bajdak-Rusinek K, Fus-Kujawa A, Kuczmik W, Gawron K. Role of extracellular matrix and inflammation in abdominal aortic aneurysm. Int J Mol Sci. 2022;23(19):11078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Haque K, Bhargava P. Abdominal Aortic Aneurysm. Am Family Phys. 2022;106(2):165–72.

    Google Scholar 

  3. Umebayashi R, Uchida HA, Wada J. Abdominal aortic aneurysm in aged population. Aging. 2018;10(12):3650–1.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sakalihasan N, Michel JB, Katsargyris A, et al. Abdominal aortic aneurysms. Nat Rev Disease Primers. 2018;4(1):34.

    Article  PubMed  Google Scholar 

  5. Renfeng Q, Shuxiao C, Peixian G, et al. ADAM10 attenuates the development of abdominal aortic aneurysms in a mouse model. Mol Med Rep. 2021;24(5):774.

    Article  PubMed  Google Scholar 

  6. Bao W, Morimoto K, Hasegawa T, et al. Orally administered dipeptidyl peptidase-4 inhibitor (alogliptin) prevents abdominal aortic aneurysm formation through an antioxidant effect in rats. J Vasc Surg. 2014;59(4):1098–108.

    Article  PubMed  Google Scholar 

  7. Wang P, Wang W, Peng X, Ruan F, Yang S. Effect of chromogranin A N-terminal fragment vasostatin-1 nano-carrier transfection on abdominal aortic aneurysm formation. Bioengineered. 2021;12(2):11018–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Keating GM. Dexmedetomidine: A Review of Its Use for Sedation in the Intensive Care Setting. Drugs. 2015;75(10):1119–30.

    Article  CAS  PubMed  Google Scholar 

  9. Qiu Z, Lu P, Wang K, et al. Dexmedetomidine inhibits neuroinflammation by altering microglial M1/M2 polarization through MAPK/ERK pathway. Neurochem Res. 2020;45(2):345–53.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Q, Liu XM, Hu Q, et al. Dexmedetomidine inhibits mitochondria damage and apoptosis of enteric glial cells in experimental intestinal ischemia/reperfusion injury via SIRT3-dependent PINK1/HDAC3/p53 pathway. J Trans Med. 2021;19(1):463.

    Article  CAS  Google Scholar 

  11. Dai M, Zhu X, Zeng S, et al. Dexmedetomidine protects cells from angiotensin II-induced smooth muscle cell phenotype switch and endothelial cell dysfunction. Cell Cycle. 2023;22(4):450–63.

    Article  CAS  PubMed  Google Scholar 

  12. Yu Q, Li Q, Yang X, et al. Dexmedetomidine suppresses the development of abdominal aortic aneurysm by downregulating the mircoRNA-21/PDCD 4 axis. Int J Mol Med. 2021;47(5):90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li YJ, Lei YH, Yao N, et al. Autophagy and multidrug resistance in cancer. Chin J Cancer. 2017;36(1):52.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wang L, Liu S, Pan B, et al. The role of autophagy in abdominal aortic aneurysm: protective but dysfunctional. Cell Cycle (Georgetown, Tex). 2020;19(21):2749–59.

    Article  CAS  PubMed  Google Scholar 

  15. Salmon M, Spinosa M, Zehner ZE, Upchurch GR, Ailawadi G. Klf4, Klf2, and Zfp148 activate autophagy-related genes in smooth muscle cells during aortic aneurysm formation. Physiol Reports. 2019;7(8):e14058.

    Article  Google Scholar 

  16. Wu QY, Cheng Z, Zhou YZ, et al. A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy. Cell Death Dis. 2020;11(2):131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li MY, Zhu XL, Zhao BX, et al. Adrenomedullin alleviates the pyroptosis of Leydig cells by promoting autophagy via the ROS-AMPK-mTOR axis. Cell Death Dis. 2019;10(7):489.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lin M, Hua R, Ma J, et al. Bisphenol A promotes autophagy in ovarian granulosa cells by inducing AMPK/mTOR/ULK1 signalling pathway. Environ Int. 2021;147:106298.

    Article  CAS  PubMed  Google Scholar 

  19. Yang T, Feng X, Zhao Y, et al. Dexmedetomidine enhances autophagy via α2-AR/AMPK/mTOR pathway to inhibit the activation of NLRP3 inflammasome and subsequently alleviates lipopolysaccharide-induced acute kidney injury. Front Pharmacol. 2020;11:790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schack AS, Stubbe J, Steffensen LB, et al. Intraluminal infusion of Penta-Galloyl Glucose reduces abdominal aortic aneurysm development in the elastase rat model. PloS One. 2020;15(8):e0234409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. He J, Li N, Fan Y, et al. Metformin inhibits abdominal aortic aneurysm formation through the activation of the AMPK/mTOR signaling pathway. J Vasc Res. 2021;58(3):148–58.

    Article  CAS  PubMed  Google Scholar 

  22. Melin LG, Dall JH, Lindholt JS, et al. Cycloastragenol inhibits experimental abdominal aortic aneurysm progression. Biomedicines. 2022;10(2):359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu H, Zhang Y, Song W, Sun Y, Jiang Y. Osteopontin N-terminal function in an abdominal aortic aneurysm from apolipoprotein E-deficient mice. Front Cell Dev Biol. 2021;9:681790.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ren J, Han Y, Ren T, et al. AEBP1 promotes the occurrence and development of abdominal aortic aneurysm by modulating inflammation via the NF-κB pathway. J Atherosclerosis Thrombosis. 2020;27(3):255–70.

    Article  CAS  Google Scholar 

  25. Wang Y, Li X, Huang X, et al. Sauchinone inhibits angiotensin II-induced proliferation and migration of vascular smooth muscle cells. Clin Exp Pharmacol Physiol. 2020;47(2):220–6.

    Article  CAS  PubMed  Google Scholar 

  26. Ramadan A, Al-Omran M, Verma S. The putative role of autophagy in the pathogenesis of abdominal aortic aneurysms. Atherosclerosis. 2017;257:288–96.

    Article  CAS  PubMed  Google Scholar 

  27. Itakura E, Mizushima N. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy. 2010;6(6):764–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bjørkøy G, Lamark T, Pankiv S, et al. Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 2009;452:181–97.

    Article  PubMed  Google Scholar 

  29. Yu Q, Zou L, Yuan X, Fang F, Xu F. Dexmedetomidine protects against septic liver injury by enhancing autophagy through activation of the AMPK/SIRT1 signaling pathway. Front Pharmacol. 2021;12:658677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao Y, Feng X, Li B, et al. Dexmedetomidine protects against lipopolysaccharide-induced acute kidney injury by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway. Front Pharmacol. 2020;11:128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ke R, Xu Q, Li C, Luo L, Huang D. Mechanisms of AMPK in the maintenance of ATP balance during energy metabolism. Cell Biol Int. 2018;42(4):384–92.

    Article  CAS  PubMed  Google Scholar 

  32. Chen M, Jing D, Ye R, Yi J, Zhao Z. PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy. Stem Cell Res Ther. 2021;12(1):566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen Y, Li Y, Li C, et al. Dexmedetomidine alleviates pain in MPTP-treated mice by activating the AMPK/mTOR/NF-κB pathways in astrocytes. Neurosci Lett. 2022;791:136933.

    Article  CAS  PubMed  Google Scholar 

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Funding

The work was supported by Science and Technology Plan Project of Jiangxi Health Commission (Grant no.202210410).

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Authors and Affiliations

  1. Department of Anesthesiology and Operative Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang, 330052, Jiangxi, China

    Qi Yu

  2. Department of General Surgery, The First Affiliated Hospital of Nanchang University, No. 1519, Dongyue Avenue, Nanchang, 330052, Jiangxi, China

    Simin Zeng, Ruilin Hu, Muqi Li, Qiang Liu, Yu Wang & Min Dai

Authors
  1. Qi Yu
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  2. Simin Zeng
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  3. Ruilin Hu
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  4. Muqi Li
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  5. Qiang Liu
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  6. Yu Wang
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  7. Min Dai
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Contributions

Min Dai conceived and designed the experiments. Min Dai, Simin Zeng, Ruilin Hu, Muqi Li, Qiang Liu, Yu Wang and Qi Yu carried out the experiments. Min Dai and Qi Yu analyzed the data. Min Dai and Qi Yu drafted the manuscript. All authors agreed to be accountable for all aspects of the work. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Min Dai.

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All animal experiments were approved by the Ethics Committee of The First Affiliated Hospital of Nanchang University and implemented following the NIH Guide for the Care and Use of Laboratory Animals.

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Yu, Q., Zeng, S., Hu, R. et al. Dexmedetomidine Alleviates Abdominal Aortic Aneurysm by Activating Autophagy Via AMPK/mTOR Pathway. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07483-8

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