Molecular and Cellular Biochemistry

, Volume 462, Issue 1–2, pp 85–96 | Cite as

The effect of propofol on hypoxia-modulated expression of heat shock proteins: potential mechanism in modulating blood–brain barrier permeability

  • Xia Sun
  • YueHao Yin
  • Lingchao Kong
  • Wei Chen
  • Changhong MiaoEmail author
  • Jiawei ChenEmail author


Heat shock proteins (HSPs) may be induced by hypoxia and alleviate blood–brain barrier (BBB) damage. The neuroprotective effect of propofol has been reported. We aimed to identify whether propofol induced HSPs expression and protected BBB integrity. Mouse astrocytes and microglia cells were cultured and exposed to hypoxia and propofol. The expression of HSP27, HSP32, HSP70, and HSP90, and the translocation of heat shock factor 1 (HSF1) and Nuclear factor-E2-related factor 2 (Nrf2) were investigated. Mouse brain microvascular endothelial cells, astrocytes, and microglial cells were co-cultured to establish in vitro BBB model, and the effects of hypoxia and propofol as well as HSPs knockdown/overexpression on BBB integrity were measured. Hypoxia (5% O2, 5% CO2, 90% humidity) treatment for 6 h and 12 h induced HSP27, HSP32, and HSP70 expression. Propofol (25 μΜ) increased HSP27 and HSP32 expression, starting with exposure to hypoxia for 3 h. Propofol induced HSF1 translocation from cytoplasmic to nuclear compartment, and blockade of HSF1 inhibited HSP27 expression in mouse astrocytes when they were exposed to hypoxia for 3 h. Propofol induced Nrf2 translocation, and blockade of Nrf2 inhibited HSP32 expression in mouse microglial cells when they were exposed to hypoxia for 3 h. Propofol protected hypoxia-impaired BBB integrity, and the effects were abolished by blockade of HSF1 and Nrf2. Overexpression of HSP27 and HSP32 alleviated hypoxia-impaired BBB integrity, and blockade of HSP27 and HSP32 expression ameliorated propofol-mediated protection against BBB impairment. Propofol may protect hypoxia-mediated BBB impairment. The mechanisms may involve HSF1-mediated HSP27 expression and Nrf2-mediated HSP32 expression.


Astrocytes Blood–brain barrier Heat shock proteins Hypoxia Microglial cells Propofol 



This work was supported by Shanghai Shenkang Hospital Development Center Clinical Science and Technology Innovation Project (SHDC12018105) and National Key R&D Program of China (No. 2018YFC2001900-04).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Daneman R (2012) The blood-brain barrier in health and disease. Ann Neurol 72:648–672CrossRefGoogle Scholar
  2. 2.
    Michinaga S, Koyama Y (2017) Protection of the blood–brain barrier as a therapeutic strategy for brain damage. Biol Pharm Bull 40(5):569–575CrossRefGoogle Scholar
  3. 3.
    Li Y, Zhong W, Jiang Z, Tang X (2019) New progress in the approaches for blood–brain barrier protection in acute ischemic stroke. Brain Res Bull 144:46–57CrossRefGoogle Scholar
  4. 4.
    Stetler RA, Gan Y, Zhang W, Liou AK, Gao Y, Cao G, Chen J (2010) Heat shock proteins: cellular and molecular mechanisms in the central nervous system. Prog Neurobiol 92(2):184–211CrossRefGoogle Scholar
  5. 5.
    Sharp FR, Zhan X, Liu DZ (2013) Heat shock proteins in the brain: role of Hsp70, Hsp 27, and HO-1 (Hsp32) and their therapeutic potential. Transl Stroke Res 4(6):685–692CrossRefGoogle Scholar
  6. 6.
    van Noort JM, Bugiani M, Amor S (2017) Heat shock proteins: old and novel roles in neurodegenerative diseases in the central nervous system. CNS Neurol Disord 16(3):244–256CrossRefGoogle Scholar
  7. 7.
    Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295(5561):1852–1858CrossRefGoogle Scholar
  8. 8.
    Dong B, Yang Y, Zhang Z, Xie K, Su L, Yu Y (2019) Hemopexin alleviates cognitive dysfunction after focal cerebral ischemia-reperfusion injury in rats. BMC Anesthesiol 19(1):13CrossRefGoogle Scholar
  9. 9.
    Ying GY, Jing CH, Li JR, Wu C, Yan F, Chen JY, Wang L, Dixon BJ, Chen G (2016) Neuroprotective effects of valproic acid on blood–brain barrier disruption and apoptosis-related early brain injury in rats subjected to subarachnoid hemorrhage are modulated by heat shock protein 70/Matrix metalloproteinases and heat shock protein 70/AKT pathways. Neurosurgery 79(2):286–295CrossRefGoogle Scholar
  10. 10.
    Shi Y, Jiang X, Zhang L, Pu H, Hu X, Zhang W, Cai W, Gao Y, Leak RK, Keep RF, Bennett MV, Chen J (2017) Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury. Proc Natl Acad Sci USA 114(7):E1243–E1252CrossRefGoogle Scholar
  11. 11.
    Xie LJ, Huang JX, Yang J, Yuan F, Zhang SS, Yu QJ, Hu J (2017) Propofol protects against blood-spinal cord barrier disruption induced by ischemia/reperfusion injury. Neural Regen Res 12:125–132CrossRefGoogle Scholar
  12. 12.
    Lu Y, Gu Y, Ding X, Wang J, Chen J, Miao C (2017) Intracellular Ca2+ homeostasis and JAK1/STAT3 pathway are involved in the protective effect of propofol on BV2 microglia against hypoxia-induced inflammation and apoptosis. PLoS ONE 12:e0178098CrossRefGoogle Scholar
  13. 13.
    Lu Y, Chen W, Lin C, Wang J, Zhu M, Chen J, Miao C (2017) The protective effects of propofol against CoCl2-induced HT22 cell hypoxia injury via PP2A/CAMKIIα/nNOS pathway. BMC Anesthesiol 17:32CrossRefGoogle Scholar
  14. 14.
    Chen W, Ju XZ, Lu Y, Ding XW, Miao CH, Chen JW (2019) Propofol improved hypoxia-impaired integrity of blood–brain barrier via modulating the expression and phosphorylation of zonula occludens-1. CNS Neurosci Ther 25(6):704–713CrossRefGoogle Scholar
  15. 15.
    Srinivasan B, Kolli AR, Esch MB, Abaci HE, Shuler ML, Hickman JJ (2015) TEER measurement techniques for in vitro barrier model systems. J Lab Autom 20(2):107–126CrossRefGoogle Scholar
  16. 16.
    Ding XW, Sun X, Shen XF, Lu Y, Wang JQ, Sun ZR, Miao CH, Chen JW (2019) Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca2+/CAMK II/ERK/NF-κB signaling pathway. Acta Pharmacol Sin. CrossRefPubMedGoogle Scholar
  17. 17.
    Parran DK, Magnin G, Li W, Jortner BS, Ehrich M (2005) Chlorpyrifos alters functional integrity and structure of an in vitro BBB model: co-cultures of bovine endothelial cells and neonatal rat astrocytes. Neurotoxicology 26(1):77–88CrossRefGoogle Scholar
  18. 18.
    Zhang J, Xia Y, Xu Z, Deng X (2016) Propofol suppressed hypoxia/reoxygenation-induced apoptosis in HBVSMC by regulation of the expression of Bcl-2, Bax, Caspase3, Kir6.1, and p-JNK. Oxid Med Cell Longev. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jha NK, Jha SK, Sharma R, Kumar D, Ambasta RK, Kumar P (2018) Hypoxia-induced signaling activation in neurodegenerative diseases: targets for new therapeutic strategies. J Alzheimers Dis 62(1):15–38CrossRefGoogle Scholar
  20. 20.
    Sun B, Ou H, Ren F, Huan Y, Zhong T, Gao M, Cai H (2018) Propofol inhibited autophagy through Ca2+/CaMKKβ/AMPK/mTOR pathway in OGD/R-induced neuron injury. Mol Med 24(1):58CrossRefGoogle Scholar
  21. 21.
    Tucker NR, Middleton RC, Le QP, Shelden EA (2011) HSF1 is essential for the resistance of zebrafish eye and brain tissues to hypoxia/reperfusion injury. PLoS ONE 6(7):e22268CrossRefGoogle Scholar
  22. 22.
    Seo JY, Pyo E, An JP, Kim J, Sung SH, Oh WK (2017) Andrographolide activates Keap1/Nrf2/ARE/HO-1 pathway in HT22 cells and suppresses microglial activation by Aβ42 through Nrf2-related inflammatory response. Mediat Inflamm 2017:5906189CrossRefGoogle Scholar
  23. 23.
    Casas AI, Geuss E, Kleikers PWM, Mencl S, Herrmann AM, Buendia I, Egea J, Meuth SG, Lopez MG, Kleinschnitz C, Schmidt HHHW (2017) NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage. Proc Natl Acad Sci USA 114(46):12315–12320CrossRefGoogle Scholar
  24. 24.
    Xu Z, Lu Y, Wang J, Ding X, Chen J, Miao C (2017) The protective effect of propofol against TNF-α-induced apoptosis was mediated via inhibiting iNOS/NO production and maintaining intracellular Ca2+ homeostasis in mouse hippocampal HT22 cells. Biomed Pharmacother 91:664–672CrossRefGoogle Scholar
  25. 25.
    Sussman ES, Connolly ES Jr (2013) Hemorrhagic transformation: a review of the rate of hemorrhage in the major clinical trials of acute ischemic stroke. Front Neurol 4:69CrossRefGoogle Scholar
  26. 26.
    Shen Y, Gu J, Liu Z, Xu C, Qian S, Zhang X, Zhou B, Guan Q, Sun Y, Wang Y, Jin X (2018) Inhibition of HIF-1α reduced blood brain barrier damage by regulating MMP-2 and VEGF during acute cerebral ischemia. Front Cell Neurosci 12:288CrossRefGoogle Scholar
  27. 27.
    Chen H, Guan B, Chen X, Chen X, Li C, Qiu J, Yang D, Liu KJ, Qi S, Shen J (2018) Baicalin attenuates blood–brain barrier disruption and hemorrhagic transformation and improves neurological outcome in ischemic stroke rats with delayed t-PA treatment: involvement of ONOO–MMP-9 pathway. Transl Stroke Res 9(5):515–529CrossRefGoogle Scholar
  28. 28.
    Mardini F, Tang JX, Li JC, Arroliga MJ, Eckenhoff RG, Eckenhoff MF (2017) Effects of propofol and surgery on neuropathology and cognition in the 3xTgAD Alzheimer transgenic mouse model. Br J Anaesth 119(3):472–480CrossRefGoogle Scholar
  29. 29.
    Kochiyama T, Li X, Nakayama H, Kage M, Yamane Y, Takamori K, Iwabuchi K, Inada E (2019) Effect of propofol on the production of inflammatory cytokines by human polarized macrophages. Mediators Inflamm 2019:1919538CrossRefGoogle Scholar
  30. 30.
    Yu H, Wang X, Kang F, Chen Z, Meng Y, Dai M (2019) Propofol attenuates inflammatory damage on neurons following cerebral infarction by inhibiting excessive activation of microglia. Int J Mol Med 43(1):452–460PubMedGoogle Scholar
  31. 31.
    Liu F, Chen MR, Liu J, Zou Y, Wang TY, Zuo YX, Wang TH (2018) Propofol administration improves neurological function associated with inhibition of pro-inflammatory cytokines in adult rats after traumatic brain injury. Neuropeptides 58:1–6CrossRefGoogle Scholar
  32. 32.
    Li C, Wang X, Cheng F, Du X, Yan J, Zhai C, Mu J, Wang Q (2019) Geniposide protects against hypoxia/reperfusion-induced blood-brain barrier impairment by increasing tight junction protein expression and decreasing inflammation, oxidative stress, and apoptosis in an in vitro system. Eur J Pharmacol 854:224–231CrossRefGoogle Scholar
  33. 33.
    Adachi H, Katsuno M, Waza M, Minamiyama M, Tanaka F, Sobue G (2009) Heat shock proteins in neurodegenerative diseases: pathogenic roles and therapeutic implications. Int J Hyperth 25(8):647–654CrossRefGoogle Scholar
  34. 34.
    Franklin TB, Krueger-Naug AM, Clarke DB, Arrigo AP, Currie RW (2005) The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. Int J Hyperth 21(5):379–392CrossRefGoogle Scholar
  35. 35.
    Stetler RA, Gao Y, Zhang L, Weng Z, Zhang F, Hu X, Wang S, Vosler P, Cao G, Sun D, Graham SH, Chen J (2012) Phosphorylation of HSP27 by protein kinase D is essential for mediating neuroprotection againstischemic neuronal injury. J Neurosci 32(8):2667–2682CrossRefGoogle Scholar
  36. 36.
    Qu Z, Titus ASCLS, Xuan Z, D’Mello SR (2018) Neuroprotection by heat shock factor-1 (HSF1) and trimerization-deficient mutant identifies novel alterations in gene expression. Sci Rep 8(1):17255CrossRefGoogle Scholar
  37. 37.
    Zhai W, Chen D, Shen H, Chen Z, Li H, Yu Z, Chen G (2016) A1 adenosine receptor attenuates intracerebral hemorrhage-induced secondary brain injury in rats by activating the P38-MAPKAP2-Hsp27 pathway. Mol Brain 9(1):66CrossRefGoogle Scholar
  38. 38.
    Shah ZA, Nada SE, Doré S (2016) Heme oxygenase 1, beneficial role in permanent ischemic stroke and in Gingko biloba (EGb 761) neuroprotection. Neuroscience 180:248–255CrossRefGoogle Scholar
  39. 39.
    Inda C, Bolaender A, Wang T, Gandu SR, Koren J 3rd (2016) Stressing out Hsp90 in neurotoxic proteinopathies. Curr Top Med Chem 16(25):2829–2838CrossRefGoogle Scholar
  40. 40.
    Blair LJ, Sabbagh JJ, Dickey CA (2014) Targeting Hsp90 and its co-chaperones to treat Alzheimer’s disease. Expert Opin Ther Targets 18(10):1219–1932CrossRefGoogle Scholar
  41. 41.
    Qi J, Liu Y, Yang P, Chen T, Liu XZ, Yin Y, Zhang J, Wang F (2015) Heat shock protein 90 inhibition by 17-Dimethylaminoethylamino-17-demethoxygeldanamycin protects blood-brain barrier integrity in cerebral ischemic stroke. Am J Transl Res 7(10):1826–1837PubMedPubMedCentralGoogle Scholar
  42. 42.
    Jiang LJ, Zhang SM, Li CW, Tang JY, Che FY, Lu YC (2017) Roles of the Nrf2/HO-1 pathway in the anti-oxidative stress response to ischemia-reperfusion brain injury in rats. Eur Rev Med Pharmacol Sci 21(7):1532–1540PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologyFudan University Shanghai Cancer CenterShanghaiPeople’s Republic of China
  2. 2.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiPeople’s Republic of China

Personalised recommendations