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Alpha2-antiplasmin deficiency affects depression and anxiety-like behavior and apoptosis induced by stress in mice

  • Yosuke Kanno ORCID logo EMAIL logo , Kaho Tsuchida , Chihiro Maruyama , Kyoko Hori , Hanako Teramura , Shiho Asahi , Osamu Matsuo and Kei-ichi Ozaki
Published/Copyright: December 16, 2021

Abstract

Objectives

Depression is a psychiatric disorder that affects about 10% of the world’s population and is accompanied by anxiety. Depression and anxiety are often caused by various stresses. However, the etiology of depression and anxiety remains unknown. It has been reported that alpha2-antiplasmin (α2AP) not only inhibits plasmin but also has various functions such as cytokine production and cell growth. This study aimed to determine the roles of α2AP on the stress-induced depression and anxiety.

Methods

We investigated the mild repeated restraint stress-induced depressive and anxiety-like behavior in the α2AP+/+ and α2AP−/− mice using the social interaction test (SIT), sucrose preference test (SPT), and elevated plus maze (EPM).

Results

The stresses such as the mild repeated restraint stress suppressed α2AP expression in the hippocampus of mice, and the treatment of fluoxetine (selective serotonin reuptake inhibitor [SSRI]) recovered the stress-caused α2AP suppression. We also showed that α2AP deficiency promoted the mild restraint stress-stimulated depression-like behavior such as social withdrawal and apathy and apoptosis in mice. In contrast, α2AP deficiency attenuated the mild restraint stress induced the anxiety-like behavior in mice.

Conclusions

α2AP affects the pathogenesis of depression and anxiety induced by stress.


Corresponding author: Yosuke Kanno, Department of Molecular Pathology, Faculty of Pharmaceutical Science, Doshisha Women’s College of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto 610-0395, Japan, Phone +81 0774 65 8629, Fax +81 0774 65 8479, E-mail: .

  1. Research funding: None.

  2. Competing interests: Authors state no conflict of interest.

  3. Ethical approval: The animal experiments were approved by the Animal Research Committee of Doshisha Women’s College of Liberal Arts (Approval ID: Y17-015, Y18-012, Y19-015). All experiments were performed in accordance with the rules and regulations of the institutions and the government.

  4. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. YK conceived and designed the experiment. YK, KT, CM, KH, HT, SA and OM were involved in the mice experiments. YK KT, CM, KH, HT and SA analyzed the data. YK, OM and KO were involved in data interpretation and writing of the manuscript.

References

1. Patel, D, Kas, M, Chattarji, S, Buwalda, B. Rodent models of social stress and neuronal plasticity: relevance to depressive-like disorders. Behav Brain Res 2019;2:369. https://doi.org/10.1016/j.bbr.2019.111900.Search in Google Scholar

2. Becker, M, Pinhasov, A, Ornoy, A. Animal models of depression: what can they teach us about the human disease? Diagnostics (Basel) 2021;11:123. https://doi.org/10.3390/diagnostics11010123.Search in Google Scholar

3. Chojnowska, S, Ptaszyńska-Sarosiek, I, Kępka, A, Knaś, M, Waszkiewicz, N. Salivary biomarkers of stress, anxiety and depression. J Clin Med 2021;10:517. https://doi.org/10.3390/jcm10030517.Search in Google Scholar

4. Nobis, A, Zalewski, D, Waszkiewicz, N. Peripheral markers of depression. J Clin Med 2020;9:3793. https://doi.org/10.3390/jcm9123793.Search in Google Scholar

5. Lucassen, P, Heine, V, Muller, M, van der Beek, E, Wiegant, V, De Kloet, E, et al.. Stress, depression and hippocampal apoptosis. CNS Neurol Disord - Drug Targets 2006;5:531–46. https://doi.org/10.2174/187152706778559273.Search in Google Scholar

6. Jeon, S, Kim, Y. The role of neuroinflammation and neurovascular dysfunction in major depressive disorder. J Inflamm Res 2018;11:179–92. https://doi.org/10.2147/jir.s141033.Search in Google Scholar

7. Capuron, L, Dantzer, R. Cytokines and depression: the need for a new paradigm. Brain Behav Immun 2003;17:S119–24. https://doi.org/10.1016/s0889-1591(02)00078-8.Search in Google Scholar

8. Geiser, F, Conrad, R, Imbierowicz, K, Meier, C, Liedtke, R, Klingmüller, D, et al.. Coagulation activation and fibrinolysis impairment are reduced in patients with anxiety and depression when medicated with serotonergic antidepressants. Psychiatr Clin Neurosci 2011;65:518–25. https://doi.org/10.1111/j.1440-1819.2011.02241.x.Search in Google Scholar

9. von Känel, R, Bellingrath, S, Kudielka, B. Association of vital exhaustion and depressive symptoms with changes in fibrin D-dimer to acute psychosocial stress. J Psychosom Res 2009;67:93–101.10.1016/j.jpsychores.2008.12.009Search in Google Scholar

10. von Känel, R. Acute mental stress and hemostasis: when physiology becomes vascular harm. Thromb Res 2015;135(Suppl 1):S52–5.10.1016/S0049-3848(15)50444-1Search in Google Scholar

11. Hoirisch-Clapauch, S. Anxiety-related bleeding and thrombosis. Semin Thromb Hemost 2018;44:656–61. https://doi.org/10.1055/s-0038-1639501.Search in Google Scholar PubMed

12. Zhao, Y, Shang, P, Wang, M, Xie, M, Liu, J. Neuroprotective effects of fluoxetine against chronic stress-induced neural inflammation and apoptosis: involvement of the p38 activity. Front Physiol 2020;11:351. https://doi.org/10.3389/fphys.2020.00351.Search in Google Scholar PubMed PubMed Central

13. Tan, X, Du, X, Jiang, Y, Botchway, B, Hu, Z, Fang, M. Inhibition of autophagy in microglia alters depressive-like behavior via BDNF pathway in postpartum depression. Front Psychiatr 2018;9:434. https://doi.org/10.3389/fpsyt.2018.00434.Search in Google Scholar PubMed PubMed Central

14. Abdul, S, Leebeek, F, Rijken, D, Uitte de Willige, S. Natural heterogeneity of α2-antiplasmin: functional and clinical consequences. Blood 2016;127:538–45. https://doi.org/10.1182/blood-2015-09-670117.Search in Google Scholar PubMed

15. Kanno, Y, Ishisaki, A, Kawashita, E, Chosa, N, Nakajima, K, Nishihara, T, et al.. Plasminogen/plasmin modulates bone metabolism by regulating the osteoblast and osteoclast function. J Biol Chem 2011;286:8952–60. https://doi.org/10.1074/jbc.m110.152181.Search in Google Scholar

16. Kanno, Y, Kawashita, E, Minamida, M, Kaneiwa, A, Okada, K, Ueshima, S, et al.. Alpha2-antiplasmin is associated with the progression of fibrosis. Am J Pathol 2010;176:238–45. https://doi.org/10.2353/ajpath.2010.090150.Search in Google Scholar PubMed PubMed Central

17. Kanno, Y, Kawashita, E, Kokado, A, Okada, K, Ueshima, S, Matsuo, O, et al.. Alpha2-antiplasmin regulates the development of dermal fibrosis in mice by prostaglandin F2α synthesis through adipose triglyceride lipase/calcium-independent phospholipase A2. Arthritis Rheum 2013;65:492–502. https://doi.org/10.1002/art.37767.Search in Google Scholar PubMed

18. Kanno, Y, Kawashita, E, Kokado, A, Kuretake, H, Ikeda, K, Okada, K, et al.. α2AP mediated myofibroblast formation and the development of renal fibrosis in unilateral ureteral obstruction. Sci Rep 2014;4:5967. https://doi.org/10.1038/srep05967.Search in Google Scholar PubMed PubMed Central

19. Menoud, P, Sappino, N, Boudal-Khoshbeen, M, Vassalli, J, Sappino, A. The kidney is a major site of alpha2-antiplasmin production. J Clin Invest 1996;97:2478–84. https://doi.org/10.1172/jci118694.Search in Google Scholar PubMed PubMed Central

20. Kanno, Y, Hirade, K, Ishisaki, A, Nakajima, K, Suga, H, Into, T, et al.. Lack of alpha2-antiplasmin improves cutaneous wound healing via over-released vascular endothelial growth factor-induced angiogenesis in wound lesions. J Thromb Haemostasis 2006;4:1602–10. https://doi.org/10.1111/j.1538-7836.2006.01978.x.Search in Google Scholar PubMed

21. Kanno, Y, Miyashita, M, Seishima, M, Matsuo, O. α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses. Immun Inflamm Dis 2020;8:267–78. https://doi.org/10.1002/iid3.302.Search in Google Scholar PubMed PubMed Central

22. Kawashita, E, Kanno, Y, Ikeda, K, Kuretake, H, Matsuo, O, Matsuno, H. Altered behavior in mice with deletion of the alpha2-antiplasmin gene. PLoS One 2014;9:e97947. https://doi.org/10.1371/journal.pone.0097947.Search in Google Scholar PubMed PubMed Central

23. Kawashita, E, Kanno, Y, Asayama, H, Okada, K, Ueshima, S, Matsuo, O, et al.. Involvement of α2-antiplasmin in dendritic growth of hippocampal neurons. J Neurochem 2013;126:58–69. https://doi.org/10.1111/jnc.12281.Search in Google Scholar PubMed

24. Okada, K, Lijnen, H, Dewerchin, M, Belayew, A, Matsuo, O, Collen, D, et al.. Characterization and targeting of the murine alpha2-antiplasmin gene. Thromb Haemostasis 1997;78:1104–10. https://doi.org/10.1055/s-0038-1657694.Search in Google Scholar

25. Kanno, Y, Into, T, Lowenstein, C, Matsushita, K. Nitric oxide regulates vascular calcification by interfering with TGF-β signalling. Cardiovasc Res 2008;77:221–30. https://doi.org/10.1093/cvr/cvm049.Search in Google Scholar PubMed

26. Huang, Y, Henry, C, Dantzer, R, Johnson, R, Godbout, J. Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiol Aging 2008;29:1744–53. https://doi.org/10.1016/j.neurobiolaging.2007.04.012.Search in Google Scholar PubMed PubMed Central

27. Jangra, A, Lukhi, M, Sulakhiya, K, Baruah, C, Lahkar, M. Protective effect of mangiferin against lipopolysaccharide-induced depressive and anxiety-like behaviour in mice. Eur J Pharmacol 2014;740:337–45. https://doi.org/10.1016/j.ejphar.2014.07.031.Search in Google Scholar PubMed

28. Kubera, M, Obuchowicz, E, Goehler, L, Brzeszcz, J, Maes, M. In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. Prog Neuro-Psychopharmacol Biol Psychiatry 2011;35:744–59. https://doi.org/10.1016/j.pnpbp.2010.08.026.Search in Google Scholar PubMed

29. Cui, M, Dai, W, Kong, J, Chen, H. Th17 Cells in depression: are they crucial for the antidepressant effect of ketamine? Front Pharmacol 2021;15:649144. https://doi.org/10.3389/fphar.2021.649144.Search in Google Scholar PubMed PubMed Central

30. Kanno, Y. The role of fibrinolytic regulators in vascular dysfunction of systemic sclerosis. Int J Mol Sci 2019;20:E619. https://doi.org/10.3390/ijms20030619.Search in Google Scholar PubMed PubMed Central

31. Ho-Tin-Noé, B, Enslen, H, Doeuvre, L, Corsi, J, Lijnen, H, Anglés-Cano, E. Role of plasminogen activation in neuronal organization and survival. Mol Cell Neurosci 2009;42:288–95. https://doi.org/10.1016/j.mcn.2009.08.001.Search in Google Scholar PubMed

32. Ho-Tin-Noé, B, Meilhac, O, Rossignol, P, Lijnen, H, Anglés-Cano, E. Dual effect of apolipoprotein(a) on plasmin(ogen)-induced apoptosis through modulation of cell detachment of adherent cells. Thromb Haemostasis 2006;95:142–50.10.1160/TH05-07-0505Search in Google Scholar

33. Kochtebane, N, Choqueux, C, Passefort, S, Nataf, P, Messika-Zeitoun, D, Bartagi, A, et al.. Plasmin induces apoptosis of aortic valvular myofibroblasts. J Pathol 2010;221:37–48. https://doi.org/10.1002/path.2681.Search in Google Scholar PubMed

34. Kanno, Y, Ishisaki, A, Kawashita, E, Kuretake, H, Ikeda, K, Matsuo, O. uPA attenuated LPS-induced inflammatory osteoclastogenesis through the plasmin/PAR-1/Ca2+/CaMKK/AMPK axis. Int J Biol Sci 2016;12:63–71. https://doi.org/10.7150/ijbs.12690.Search in Google Scholar PubMed PubMed Central

35. Moran, T. Anxiety and working memory capacity: a meta-analysis and narrative review. Psychol Bull 2016;142:831–64. https://doi.org/10.1037/bul0000051.Search in Google Scholar PubMed

36. Lukasik, K, Waris, O, Soveri, A, Lehtonen, M, Laine, M. The relationship of anxiety and stress with working memory performance in a large non-depressed sample. Front Psychol 2019;23:4. https://doi.org/10.3389/fpsyg.2019.00004.Search in Google Scholar PubMed PubMed Central

Received: 2021-09-15
Accepted: 2021-11-26
Published Online: 2021-12-16

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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