Intermittent hypoxia reduces microglia proliferation and induces DNA damage in vitro | ||
| Iranian Journal of Basic Medical Sciences | ||
| مقاله 6، دوره 19، شماره 5، مرداد 2016، صفحه 497-502 اصل مقاله (1.07 M) | ||
| نوع مقاله: Original Article | ||
| شناسه دیجیتال (DOI): 10.22038/ijbms.2016.6934 | ||
| نویسندگان | ||
| Song Liu* 1؛ Zhonghua Wang2؛ Bo Xu3؛ Kui Chen4؛ Jinyuan Sun1؛ Lianping Ren1 | ||
| 1Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China, 200092 | ||
| 2Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China, 200032 | ||
| 3Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China, 100050 | ||
| 4Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China, 100050 | ||
| چکیده | ||
| Objective(s):Intermittent hypoxia (IH), caused by obstructive sleep apnea (OSA), could cause hippocampus or neuron damage through multiple signaling pathways, while the underlying mechanisms are still unclear. Thus, the present study aimed to explore the effect of IH on the biological functions of microglia cells. Materials and Methods:Cell proliferation of BV2 cells after exposure to IH were observed by MTT assay and then DNA damage was detected by comet assay. RNA-sequencing assay was performed in cells under IH condition and normal conditions to find out the differentially expressed genes, which were further confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot assay. Results:As results, IH inhibited the proliferation of BV2 cells, as well as caused DNA damage. RNA-sequencing assay revealed 4 differentially expressed genes (p21, Cyclin D1, Cyclin E2, and Gadd45α) which were associated with the network of P53 signaling pathways in BV2 cells, among which, p21 and Gadd45α were dramatically increased while Cyclin D1 and Cyclin E2 were both decreased significantly. Moreover, inflammatory factors including IL-6, TNF-α and iNOS were significantly up-regulated in microglia cells under IH conditions for 8 hr. Conclusion:Our results indicated that IH could inhibit cyclin D1 and cyclin E2 expression via initiating multiple P53 pathways, which further blocked cell cycle transition and attenuated proliferative capability of BV2 cells. Meanwhile, IH activated inflammation reactions in BV2 cells. Present study elaborate the effects of IH on biological functions of microglia and provide theoretical foundation for further study on new therapy methods for OSA. | ||
| کلیدواژهها | ||
| Inflammatory cytokine؛ Intermittent hypoxia؛ Microglia؛ P53 signaling pathways | ||
| مراجع | ||
|
1. Yang Q, Wang Y, Feng J, Cao J, Chen B. Intermittent hypoxia from obstructive sleep apnea may cause neuronal impairment and dysfunction in central nervous system: the potential roles played by microglia. Neuropsych Dis Treat 2013; 9:1077-1086.
2. Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 2005; 9:211-224.
3. Décary A, Rouleau I, Montplaisir J. Cognitive deficits associated with sleep apnea syndrome: a proposed neuropsychological test battery. Sleep 2000; 23:369-381.
4. Kheirandish-Gozal L, De Jong MR, Spruyt K, Chamuleau SA, Gozal D. Obstructive sleep apnoea is associated with impaired pictorial memory task acquisition and retention in children. Eur Respir J 2010; 36:164-9.
5. Zhang SXL, Wang Y, Gozal D. Pathological consequences of intermittent hypoxia in the central nervous system: John Wiley & Sons, Inc., 2012.
6. Kim SM, Kim H, Lee JS, Park KS, Jeon GS, Shon J, et al. Intermittent hypoxia can aggravate motor neuronal loss and cognitive dysfunction in ALS mice. PLoS One 2013; 8(11): e81808.
7. Paolicelli RC, Bisht K, Tremblay Mv. Fractalkine regulation of microglial physiology and consequences on the brain and behavior. Front Cell Neurosci 2014; 8:129.
8. Skaper SD, Facci L, Giusti P. Neuroinflammation, microglia and mast cells in the pathophysiology of neurocognitive disorders: a review. Cns Neurol Disord-DR 2014; 13:1654-1666.
9. Schwartz M, Baruch K. Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: Boosting autoimmunity to fight-off chronic neuroinflammation. J Autoimmun 2014; 54:8–14.
10. Da FA, Matias D, Garcia C, Amaral R, Geraldo LH, Freitas C, et al. The impact of microglial activation on blood-brain barrier in brain diseases. Front Cell Neurosci 2014; 8:362.
11. Malm TM, Jay TR, Landreth GE. The evolving biology of microglia in Alzheimer’s disease. Neurotherapeutics 2015; 12:1-13.
12. Prout AP, Frasch MG, Veldhuizen RAW, Hammond R, Ross MG, Richardson BS. Systemic and cerebral inflammatory response to umbilical cord occlusions with worsening acidosis in the ovine fetus. Am J Obstet Gynecol 2010; 202:765-768. 13. Zhou HH, Xiao Y, Chen BC, Jia Z, Zhao B. Biological function of primary cultured microgliacell in differet stages during anoxia. J Neurosci Ment Health 2011; 11:362-364.
14. Hollander MC, Kovalsky O, Salvador JM, Kim KE, Patterson AD, Haines DC, et al. Dimethylbenzanthracene carcinogenesis in Gadd45a-null mice is associated with decreased DNA repair and increased mutation frequency. Cancer Res 2001; 61:2487-2491.
15. Narayanan BA, Geoffroy O, Willingham MC, Re GG, Nixon DW. p53/p21(WAF1/CIP1) expression and its possible role in G1 arrest and apoptosis in ellagic acid treated cancer cells. Cancer Lett 1999; 136:215-221.
16. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature 1993; 366:701-704.
17. Tao Y, Song X, Deng X, Xie D, Lee LM, Liu Y, et al. Nuclear accumulation of epidermal growth factor receptor and acceleration of G1/S stage by Epstein-Barr-encoded oncoprotein latent membrane protein 1. Exp Cell Res 2005; 303:240-251.
18. Q Z, I B, MB K, Jr FA. The p53-dependent gamma-ray response of GADD45. Cancer Res 1994; 54:2755-2760.
19. Kastan MB, Zhan Q, El-Deiry WS, Carrier F, Jacks T, Walsh WV, et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 1992; 71:587-597.
20. Choi HJ, Kang KS, Fukui M, Zhu BT. Critical role of the JNK-p53-GADD45α apoptotic cascade in mediating oxidative cytotoxicity in hippocampal neurons. Brit J Pharmacol 2011; 162:175–192.
21. Okura T, Nakamura M, Takata Y, Watanabe S, Kitami Y, Hiwada K. Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells. Eur J Pharmacol 2000; 407:227–235.
22. Smith ML, Ford JM, Hollander MC, Bortnick RA, Amundson SA, Seo YR, et al. p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes. Mol Cell Biol 2000; 20: 3705-3714.
23. Row BW, Liu R, Xu W, Kheirandish L, Gozal D. Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med 2003; 167:1548-1553.
24. Li RC, Row BW, Kheirandish L, Brittian KR, Gozal E, Guo SZ, et al. Nitric oxide synthase and intermittent hypoxia-induced spatial learning deficits in the rat. Neurobiol Dis 2004; 17:44-53.
25. Smith SM, Friedle SA, Watters JJ. Chronic intermittent hypoxia exerts CNS region-specific effects on rat microglial inflammatory and TLR4 gene expression. Plos One 2013; 8:182.
26. Hill KE, Zollinger LV, Watt HE, Carlson NG, Rose JW. Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. J Neuroimmunol 2004; 151:171–179. | ||
|
آمار تعداد مشاهده مقاله: 1,240 تعداد دریافت فایل اصل مقاله: 1,141 |
||