Tanshinone IIA Suppresses Hypoxia-induced Apoptosis in Medial Vestibular Nucleus Cells Via a Skp2/BKCa Axis

Author(s): Jing-Jing Zhu, Shu-Hui Wu, Xiang Chen, Ting-Ting Jiang, Xin-Qian Li, Jing-Min Li, Yong Yan, Xue-Jun Wu, Yu-Ying Liu, Pin Dong*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 33 , 2020


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Abstract:

Background: The aim of the present study was to investigate the protective effects of Tanshinone IIA (Tan IIA) on hypoxia-induced injury in the medial vestibular nucleus (MVN) cells.

Methods: An in vitro hypoxia model was established using MVN cells exposed to hypoxia. The hypoxia-induced cell damage was confirmed by assessing cell viability, apoptosis and expression of apoptosis-associated proteins. Oxidative stress and related indicators were also measured following hypoxia modeling and Tan IIA treatment, and the genes potentially involved in the response were predicted using multiple GEO datasets.

Results: The results of the present study showed that Tan IIA significantly increased cell viability, decreased cell apoptosis and decreased the ratio of Bax/Bcl-2 in hypoxia treated cells. In addition, hypoxia treatment increased oxidative stress in MVN cells, and treatment with Tan IIA reduced the oxidative stress. The expression of SPhase Kinase Associated Protein 2 (SKP2) was upregulated in hypoxia treated cells, and Tan IIA treatment reduced the expression of SKP2. Mechanistically, SKP2 interacted with large-conductance Ca2+-activated K+ channels (BKCa), regulating its expression, and BKCa knockdown alleviated the protective effects of Tan IIA on hypoxia induced cell apoptosis.

Conclusion: The results of the present study suggested that Tan IIA had a protective effect on hypoxia-induced cell damage through its anti-apoptotic and anti-oxidative activity via an SKP2/BKCa axis. These findings suggest that Tan IIA may be a potential therapeutic for the treatment of hypoxia-induced vertigo.

Keywords: S-Phase Kinase Associated Protein 2, large-conductance Ca2+-activated K+ channels, Tanshinone IIA, medial vestibular nucleus, hypoxia, cell apoptosis.

[1]
Goldberg JM, Smith CE, Fernández C. Relation between discharge regularity and responses to externally applied galvanic currents in vestibular nerve afferents of the squirrel monkey. J Neurophysiol 1984; 51(6): 1236-56.
[http://dx.doi.org/10.1152/jn.1984.51.6.1236] [PMID: 6737029]
[2]
Cazin L, Precht W, Lannou J. Firing characteristics of neurons mediating optokinetic responses to rat’s vestibular neurons. Pflugers Arch 1980; 386(3): 221-30.
[http://dx.doi.org/10.1007/BF00587472] [PMID: 6968430]
[3]
Kim JS, Lee H. Inner ear dysfunction due to vertebrobasilar ischemic stroke. Semin Neurol 2009; 29(5): 534-40.
[http://dx.doi.org/10.1055/s-0029-1241037] [PMID: 19834865]
[4]
Xie H, Zhang YQ, Pan XL, et al. Decreased calcium-activated potassium channels by hypoxia causes abnormal firing in the spontaneous firing medial vestibular nuclei neurons. Eur Arch Otorhinolaryngol 2015; 272(10): 2703-11.
[http://dx.doi.org/10.1007/s00405-014-3158-4] [PMID: 25173490]
[5]
Smith MR, Nelson AB, Du Lac S. Regulation of firing response gain by calcium-dependent mechanisms in vestibular nucleus neurons. J Neurophysiol 2002; 87(4): 2031-42.
[http://dx.doi.org/10.1152/jn.00821.2001] [PMID: 11929921]
[6]
Zhao M, Zhu P, Fujino M, et al. Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies. Int J Mol Sci 2016; 17(12): 17.
[http://dx.doi.org/10.3390/ijms17122078] [PMID: 27973415]
[7]
Chen R, Lai UH, Zhu L, Singh A, Ahmed M, Forsyth NR. Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors. Front Cell Dev Biol 2018; 6: 132.
[http://dx.doi.org/10.3389/fcell.2018.00132] [PMID: 30364203]
[8]
Sonego G, Abonnenc M, Tissot JD, Prudent M, Lion N. Redox proteomics and platelet activation: Understanding the redox proteome to improve platelet quality for transfusion. Int J Mol Sci 2017; 18(2): 18.
[http://dx.doi.org/10.3390/ijms18020387] [PMID: 28208668]
[9]
Hill MA, Braun AP. Oxidant signaling underlies PKGIα modulation of Ca2+ sparks and BKCa in myogenically active arterioles. Sci Signal 2016; 9(449): fs15.
[http://dx.doi.org/10.1126/scisignal.aak9385] [PMID: 27729549]
[10]
Hou S, Heinemann SH, Hoshi T. Modulation of BKCa channel gating by endogenous signaling molecules. Physiology (Bethesda) 2009; 24: 26-35.
[http://dx.doi.org/10.1152/physiol.00032.2008] [PMID: 19196649]
[11]
Baker D, Pryce G, Visintin C, et al. Big conductance calcium-activated potassium channel openers control spasticity without sedation. Br J Pharmacol 2017; 174(16): 2662-81.
[http://dx.doi.org/10.1111/bph.13889] [PMID: 28677901]
[12]
Gao N, Wang H, Zhang X, Yang Z. The inhibitory effect of angiotensin II on BKCa channels in podocytes via oxidative stress. Mol Cell Biochem 2015; 398(1-2): 217-22.
[http://dx.doi.org/10.1007/s11010-014-2221-1] [PMID: 25234195]
[13]
Zhang R, Sun H, Liao C, et al. Chronic hypoxia in cultured human podocytes inhibits BKCa channels by upregulating its β4-subunit. Biochem Biophys Res Commun 2012; 420(3): 505-10.
[http://dx.doi.org/10.1016/j.bbrc.2012.03.021] [PMID: 22446331]
[14]
Yan SH, Zhao NW, Geng ZR, et al. Modulations of Keap1-Nrf2 signaling axis by TIIA ameliorated the oxidative stress-induced myocardial apoptosis. Free Radic Biol Med 2018; 115: 191-201.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.12.001] [PMID: 29221988]
[15]
Sun S, Yin Y, Yin X, et al. Anti-nociceptive effects of Tanshinone IIA (TIIA) in a rat model of complete Freund’s adjuvant (CFA)-induced inflammatory pain. Brain Res Bull 2012; 88(6): 581-8.
[http://dx.doi.org/10.1016/j.brainresbull.2012.06.002] [PMID: 22705002]
[16]
Chang CC, Kuan CP, Lin JY, Lai JS, Ho TF. Tanshinone IIA Facilitates TRAIL Sensitization by Up-regulating DR5 through the ROS-JNK-CHOP Signaling Axis in Human Ovarian Carcinoma Cell Lines. Chem Res Toxicol 2015; 28(8): 1574-83.
[http://dx.doi.org/10.1021/acs.chemrestox.5b00150] [PMID: 26203587]
[17]
Him A, Altuntaş S, Öztürk G, Erdoğan E, Cengiz N. Isolation and culture of adult mouse vestibular nucleus neurons. Turk J Med Sci 2017; 47(6): 1903-11.
[http://dx.doi.org/10.3906/sag-1706-158] [PMID: 29306256]
[18]
Liu L, Zhang K, Sandoval H, et al. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell 2015; 160(1-2): 177-90.
[http://dx.doi.org/10.1016/j.cell.2014.12.019] [PMID: 25594180]
[19]
Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB. Transcranial amelioration of inflammation and cell death after brain injury. Nature 2014; 505(7482): 223-8.
[http://dx.doi.org/10.1038/nature12808] [PMID: 24317693]
[20]
Candelario-Jalil E. Injury and repair mechanisms in ischemic stroke: considerations for the development of novel neurotherapeutics. Curr Opin Investig Drugs 2009; 10(7): 644-54.
[PMID: 19579170]
[21]
Cao YF, Wang SF, Li X, Zhang YL, Qiao YJ. The anticancer mechanism investigation of Tanshinone IIA by pharmacological clustering in protein network. BMC Syst Biol 2018; 12(1): 90.
[http://dx.doi.org/10.1186/s12918-018-0606-6] [PMID: 30373594]
[22]
Sui H, Zhao J, Zhou L, et al. Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in human colorectal cancer. Cancer Lett 2017; 403: 86-97.
[http://dx.doi.org/10.1016/j.canlet.2017.05.013] [PMID: 28602978]
[23]
Lv C, Zeng HW, Wang JX, et al. The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG. Cell Death Dis 2018; 9(2): 165.
[http://dx.doi.org/10.1038/s41419-017-0247-5] [PMID: 29416003]
[24]
Zhu H, Chen Z, Ma Z, et al. Tanshinone IIA Protects Endothelial Cells from H2O2-Induced Injuries via PXR Activation. Biomol Ther (Seoul) 2017; 25(6): 599-608.
[http://dx.doi.org/10.4062/biomolther.2016.179] [PMID: 28173640]
[25]
Luo Y, Xu DQ, Dong HY, et al. Tanshinone IIA inhibits hypoxia induced pulmonary artery smooth muscle cell proliferation via Akt/Skp2/p27-associated pathway. PLoS One 2013; 8(2)e56774
[http://dx.doi.org/10.1371/journal.pone.0056774] [PMID: 23437233]
[26]
Liu T, Jin H, Sun QR, Xu JH, Hu HT. The neuroprotective effects of tanshinone IIA on β-amyloid-induced toxicity in rat cortical neurons. Neuropharmacology 2010; 59(7-8): 595-604.
[http://dx.doi.org/10.1016/j.neuropharm.2010.08.013] [PMID: 20800073]
[27]
Tang N, Chang J, Zeng Y, Zheng J. Tanshinone IIA protects hypoxia-induced injury by preventing microRNA-28 up-regulation in PC-12 cells. Eur J Pharmacol 2019; 854: 265-71.
[http://dx.doi.org/10.1016/j.ejphar.2019.04.030] [PMID: 31002779]
[28]
Dal-Cim T, Martins WC, Santos AR, Tasca CI. Guanosine is neuroprotective against oxygen/glucose deprivation in hippocampal slices via large conductance Ca2+-activated K+ channels, phosphatidilinositol-3 kinase/protein kinase B pathway activation and glutamate uptake. Neuroscience 2011; 183: 212-20.
[http://dx.doi.org/10.1016/j.neuroscience.2011.03.022] [PMID: 21435378]
[29]
Su F, Guo AC, Li WW, et al. Low-dose ethanol preconditioning protects against oxygen-glucose deprivation/reoxygenation-induced neuronal injury by activating large conductance, Ca2+-activated K+ channels in vitro. Neurosci Bull 2017; 33(1): 28-40.
[http://dx.doi.org/10.1007/s12264-016-0080-3] [PMID: 27854008]
[30]
Chen Y, Yan X, Guo Q, et al. [Effects of sowing date on morphologic characteristics, yield and quality of Radix isatidis]. Zhongguo Zhongyao Zazhi 2009; 34(21): 2709-12. [Effects of sowing date on morphologic characteristics, yield and quality of Radix isatidis]
[PMID: 20209897]
[31]
Chen M, Sun HY, Hu P, et al. Activation of BKca channels mediates hippocampal neuronal death after reoxygenation and reperfusion. Mol Neurobiol 2013; 48(3): 794-807.
[http://dx.doi.org/10.1007/s12035-013-8467-x] [PMID: 23653329]


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Article Details

VOLUME: 26
ISSUE: 33
Year: 2020
Published on: 23 September, 2020
Page: [4185 - 4194]
Pages: 10
DOI: 10.2174/1381612826666200602144405
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