Skip to main content

The Protective Mechanism of Dexmedetomidine in Regulating Atg14L-Beclin1-Vps34 Complex Against Myocardial Ischemia-Reperfusion Injury

Abstract

The blood flow restoration of ischemic tissues causes myocardial injury. Dexmedetomidine (Dex) protects multi-organs against ischemia/reperfusion (I/R) injury. This study investigated the protective mechanism of Dex post-treatment in myocardial I/R injury. The rat model of myocardial I/R was established. The effects of Dex post-treatment on cardiac function and autophagy flow were observed. Dex attenuated myocardial I/R injury and reduced I/R-induced autophagy in rats. Dex weakened the interactions between Beclin1 and Vps34 and Beclin1 and Atg14L, thus downregulating Vps34 kinase activity. In vitro, the cardiomyocytes subjected to oxygen glucose deprivation/reoxygenation were treated with Dex and PI3K inhibitor LY294002. LY294002 attenuated the myocardial protective effect of DEX, indicating that Dex protected against cardiac I/R by activating the PI3K/Akt pathway. In conclusion, Dex upregulated the phosphorylation of Beclin1 at S295 site by activating the PI3K/Akt pathway and reduced the interactions of Atg14L-Beclin1-Vps34 complex, thus inhibiting autophagy and protecting against myocardial I/R injury.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Data Availability

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

References

  1. 1.

    Lu, L., Liu, M., Sun, R., et al. (2015). Myocardial infarction: Symptoms and treatments. Cell Biochemistry and Biophysics, 72(3), 865–867.

    CAS  PubMed  Google Scholar 

  2. 2.

    Frank, A., Bonney, M., Bonney, S., et al. (2012). Myocardial ischemia reperfusion injury: From basic science to clinical bedside. Seminars in Cardiothoracic and Vascular Anesthesia, 16(3), 123–132.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Nobian, A., Mohamed, A., & Spyridopoulos, I. (2019). The role of arginine vasopressin in myocardial infarction and reperfusion. Kardiologia Polska, 77(10), 908–917.

    PubMed  Google Scholar 

  4. 4.

    Caccioppo, A., Franchin, L., Grosso, A., et al. (2019). Ischemia reperfusion injury: Mechanisms of damage/protection and novel strategies for cardiac recovery/regeneration. International Journal of Molecular Sciences, 20(20), 5024.

  5. 5.

    Decuypere, J. P., Ceulemans, L. J., Agostinis, P., et al. (2015). Autophagy and the kidney: Implications for ischemia-reperfusion injury and therapy. American Journal of Kidney Diseases, 66(4), 699–709.

    PubMed  Google Scholar 

  6. 6.

    Xie, M., Morales, C. R., Lavandero, S., & Hill, J. A. (2011). Tuning flux: autophagy as a target of heart disease therapy. Current Opinion in Cardiology, 26(3), 216–222.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Li, X., Hu, X., Wang, J., et al. (2018). Inhibition of autophagy via activation of PI3K/Akt/mTOR pathway contributes to the protection of hesperidin against myocardial ischemia/reperfusion injury. International Journal of Molecular Medicine, 42(4), 1917–1924.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Aghaei, M., Motallebnezhad, M., Ghorghanlu, S., et al. (2019). Targeting autophagy in cardiac ischemia/reperfusion injury: A novel therapeutic strategy. Journal of Cellular Physiology, 234(10), 16768–16778.

    CAS  PubMed  Google Scholar 

  9. 9.

    Lamark, T., & Johansen, T. (2012). Aggrephagy: selective disposal of protein aggregates by macroautophagy. International Journal of Cell Biology, 2012, 736905.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Ma, B., Cao, W., Li, W., et al. (2014). Dapper1 promotes autophagy by enhancing the Beclin1-Vps34-Atg14L complex formation. Cell Research, 24(8), 912–924.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Pyo, K. E., Kim, C. R., Lee, M., et al. (2018). ULK1 O-GlcNAcylation is crucial for activating VPS34 via ATG14L during autophagy initiation. Cell Reports, 25(10), 2878–2890 e4.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Li, A., Yuen, V. M., Goulay-Dufay, S., & Kwok, P. C. (2016). Pharmacokinetics and pharmacodynamics of dexmedetomidine. Drug Development and Industrial Pharmacy, 42(12), 1917–1927.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Wang, Y., Wu, S., Yu, X., et al. (2016). Dexmedetomidine protects rat liver against ischemia-reperfusion injury partly by the alpha2A-adrenoceptor subtype and the mechanism is associated with the TLR4/NF-kappaB pathway. International Journal of Molecular Sciences, 17(7), 995.

  14. 14.

    Sun, Z., Zhao, T., Lv, S., et al. (2018). Dexmedetomidine attenuates spinal cord ischemia-reperfusion injury through both anti-inflammation and anti-apoptosis mechanisms in rabbits. Journal of Translational Medicine, 16(1), 209.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Liang, J., Zhang, X. Y., Zhen, Y. F., et al. (2019). PGK1 depletion activates Nrf2 signaling to protect human osteoblasts from dexamethasone. Cell Death & Disease, 10(12), 888.

    Google Scholar 

  16. 16.

    Cheng, J., Zhu, P., Qin, H., et al. (2018). Dexmedetomidine attenuates cerebral ischemia/reperfusion injury in neonatal rats by inhibiting TLR4 signaling. The Journal of International Medical Research, 46(7), 2925–2932.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Cai, Y., Xu, H., Yan, J., et al. (2014). Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury. Molecular Medicine Reports, 9(5), 1542–1550.

    CAS  Google Scholar 

  18. 18.

    Zhang, W., & Zhang, J. (2017). Dexmedetomidine preconditioning protects against lung injury induced by ischemia-reperfusion through inhibition of autophagy. Experimental and Therapeutic Medicine, 14(2), 973–980.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Zhang, X., Li, Y., Wang, Y., et al. (2020). Dexmedetomidine postconditioning suppresses myocardial ischemia/reperfusion injury by activating the SIRT1/mTOR axis. Bioscience Reports, 40(5), BSR20194030.

  20. 20.

    Yu, T., Liu, D., Gao, M., et al. (2019). Dexmedetomidine prevents septic myocardial dysfunction in rats via activation of alpha7nAChR and PI3K/Akt- mediated autophagy. Biomedicine & Pharmacotherapy, 120, 109231.

    CAS  Google Scholar 

  21. 21.

    Witlin, L. T. (1988). 1987 Schwartz award. Countersuits by medical malpractice defendants against attorneys. The Journal of Legal Medicine, 9(3), 421–447.

    CAS  PubMed  Google Scholar 

  22. 22.

    Peng, K., Chen, W. R., Xia, F., et al. (2020). Dexmedetomidine post-treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF-1alpha signalling. Journal of Cellular and Molecular Medicine, 24(1), 850–861.

    CAS  PubMed  Google Scholar 

  23. 23.

    Cheng, X. Y., Gu, X. Y., Gao, Q., et al. (2016). Effects of dexmedetomidine postconditioning on myocardial ischemia and the role of the PI3K/Akt-dependent signaling pathway in reperfusion injury. Molecular Medicine Reports, 14(1), 797–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Cheng, X., Hu, J., Wang, Y., et al. (2018). Effects of dexmedetomidine postconditioning on myocardial ischemia/reperfusion injury in diabetic rats: role of the PI3K/Akt-dependent signaling pathway. Journal Diabetes Research, 2018, 3071959.

    Google Scholar 

  25. 25.

    Bunte, S., Behmenburg, F., Majewski, N., et al. (2020). Characteristics of dexmedetomidine postconditioning in the field of myocardial ischemia-reperfusion injury. Anesthesia and Analgesia, 130(1), 90–98.

    CAS  PubMed  Google Scholar 

  26. 26.

    Zhu, Y., Li, S., Liu, J., et al. (2019). Role of JNK signaling pathway in dexmedetomidine post-conditioning-induced reduction of the inflammatory response and autophagy effect of focal cerebral ischemia reperfusion injury in rats. Inflammation, 42(6), 2181–2191.

    CAS  PubMed  Google Scholar 

  27. 27.

    Zhao, Y., Feng, X., Li, B., et al. (2020). Dexmedetomidine protects against lipopolysaccharide-induced acute kidney injury by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway. Frontiers in Pharmacology, 11, 128.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Luo, C., Ouyang, M. W., Fang, Y. Y., et al. (2017). Dexmedetomidine protects mouse brain from ischemia-reperfusion injury via inhibiting neuronal autophagy through up-regulating HIF-1alpha. Frontiers in Cellular Neuroscience, 11, 197.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Lempiainen, J., Finckenberg, P., Mervaala, E. E., et al. (2014). Dexmedetomidine preconditioning ameliorates kidney ischemia-reperfusion injury. Pharmacology Research & Perspectives, 2(3), e00045.

    Google Scholar 

  30. 30.

    Kang, R., Zeh, H. J., Lotze, M. T., & Tang, D. (2011). The Beclin 1 network regulates autophagy and apoptosis. Cell Death and Differentiation, 18(4), 571–580.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Menon, M. B., & Dhamija, S. (2018). Beclin 1 phosphorylation - At the center of autophagy regulation. Frontiers in Cell and Development Biology, 6, 137.

    Google Scholar 

  32. 32.

    Wang, R. C., Wei, Y., An, Z., et al. (2012). Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science, 338(6109), 956–959.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Boag, S. E., Andreano, E., & Spyridopoulos, I. (2017). Lymphocyte communication in myocardial ischemia/reperfusion injury. Antioxidants & Redox Signaling, 26(12), 660–675.

    CAS  Google Scholar 

  34. 34.

    Mokhtari-Zaer, A., Marefati, N., Atkin, S. L., et al. (2018). The protective role of curcumin in myocardial ischemia-reperfusion injury. Journal of Cellular Physiology, 234(1), 214–222.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Sun, Y., Yi, W., Yuan, Y., et al. (2013). C1q/tumor necrosis factor-related protein-9, a novel adipocyte-derived cytokine, attenuates adverse remodeling in the ischemic mouse heart via protein kinase A activation. Circulation, 128(11 Suppl 1), S113–S120.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Wong, W. W., & Puthalakath, H. (2008). Bcl-2 family proteins: The sentinels of the mitochondrial apoptosis pathway. IUBMB Life, 60(6), 390–397.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Zhang, J., Jiang, H., Liu, D. H., & Wang, G. N. (2019). Effects of dexmedetomidine on myocardial ischemia-reperfusion injury through PI3K-Akt-mTOR signaling pathway. European Review for Medical and Pharmacological Sciences, 23(15), 6736–6743.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Shi, B., Ma, M., Zheng, Y., et al. (2019). mTOR and Beclin1: Two key autophagy-related molecules and their roles in myocardial ischemia/reperfusion injury. Journal of Cellular Physiology, 234(8), 12562–12568.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Osawa, T., Kotani, T., Kawaoka, T., et al. (2019). Atg2 mediates direct lipid transfer between membranes for autophagosome formation. Nature Structural & Molecular Biology, 26(4), 281–288.

    CAS  Google Scholar 

  40. 40.

    Shan, Y., Sun, S., Yang, F., et al. (2018). Dexmedetomidine protects the developing rat brain against the neurotoxicity wrought by sevoflurane: Role of autophagy and Drp1-Bax signaling. Drug Design, Development and Therapy, 12, 3617–3624.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Tang, Y., Jia, C., He, J., et al. (2019). The application and analytical pathway of dexmedetomidine in ischemia/reperfusion injury. Journal of Analytical Methods in Chemistry, 2019, 7158142.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Noda, T., Matsunaga, K., & Yoshimori, T. (2011). Atg14L recruits PtdIns 3-kinase to the ER for autophagosome formation. Autophagy, 7(4), 438–439.

    PubMed  Google Scholar 

  43. 43.

    Russell, R. C., Tian, Y., Yuan, H., et al. (2013). ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nature Cell Biology, 15(7), 741–750.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Backer, J. M. (2008). The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochemical Journal, 410(1), 1–17.

    CAS  Google Scholar 

  45. 45.

    Wang, B. J., Zheng, W. L., Feng, N. N., et al. (2018). The effects of autophagy and PI3K/AKT/m-TOR signaling pathway on the cell-cycle arrest of rats primary sertoli cells induced by zearalenone. Toxins (Basel), 10(10), 398.

  46. 46.

    Sun, Y., Jiang, C., Jiang, J., & Qiu, L. (2017). Dexmedetomidine protects mice against myocardium ischaemic/reperfusion injury by activating an AMPK/PI3K/Akt/eNOS pathway. Clinical and Experimental Pharmacology & Physiology, 44(9), 946–953.

    CAS  Google Scholar 

  47. 47.

    Shen, M., Wang, S., Wen, X., et al. (2017). Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury. Biomedicine & Pharmacotherapy, 95, 885–893.

    CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

Conceptualization: YL and MQ; validation, research, resources, data reviewing, and writing: FX, HL, and DC; review and editing: NX and WZ. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Na Xing or Wei Zhang.

Ethics declarations

Ethics Approval and Consent to Participate

This study got the permission of the Ethical Committee of the First Affiliated Hospital of Zhengzhou University. All the animal experiments were implemented on the guide for the care and use of laboratory animals.

Patient Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Associate Editor Nicola Smart oversaw the review of this article

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Qu, M., Xing, F. et al. The Protective Mechanism of Dexmedetomidine in Regulating Atg14L-Beclin1-Vps34 Complex Against Myocardial Ischemia-Reperfusion Injury. J. of Cardiovasc. Trans. Res. 14, 1063–1074 (2021). https://doi.org/10.1007/s12265-021-10125-9

Download citation

Keywords

  • Dexmedetomidine
  • Myocardium
  • Ischemia/reperfusion
  • Autophagy
  • PI3K/Akt pathway
  • Beclin1
  • Vps34
  • LY294002