The effect of propofol on hypoxia-modulated expression of heat shock proteins: potential mechanism in modulating blood–brain barrier permeability
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.
KeywordsAstrocytes 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).
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Conflict of interest
The authors declare that they have no conflict of interest.
- 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.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
- 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. https://doi.org/10.1038/s41401-019-0258-0 CrossRefPubMedGoogle Scholar
- 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
- 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
- 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