Thioredoxin-interacting protein mediates mitochondrion-dependent apoptosis in early brain injury after subarachnoid hemorrhage
Early brain injury (EBI) was reported to be the primary cause of high mortality and poor outcomes in subarachnoid hemorrhage (SAH) patients, and apoptosis is regarded as the most important physiopathologic mechanism during EBI. Recently, our team found that thioredoxin-interacting protein (TXNIP) links endoplasmic reticulum stress (ER stress) to neuronal apoptosis and aggravates EBI. However, the other underlying mechanisms remain unknown. Mitochondria are considered to be the central points in integrating apoptotic cell death. However, whether crosstalk between TXNIP and the mitochondria-mediated intrinsic apoptotic pathway is effective on EBI has not been previously reported. Therefore, we created an endovascular perforation SAH model in Sprague–Dawley rats to determine the possible mechanism. We found that TXNIP expression in apoptotic neurons significantly increased in the SAH group compared with the sham group. In addition, increased TXNIP expression was accompanied by remarkable changes in mitochondrial-related antiapoptotic and proapoptotic factors. Furthermore, resveratrol (RES, a TXNIP inhibitor) administration significantly downregulated the expression of TXNIP and mitochondria-related proapoptotic factors. Additionally, it attenuated SAH prognostic indicators, such as brain edema, blood–brain barrier permeability, and neurological deficits. Therefore, our study further confirms that TXNIP may participate in neuronal apoptosis through the mitochondrial signaling pathway and that TXNIP may be a target for SAH treatment.
KeywordsSubarachnoid hemorrhage Early brain injury Thioredoxin-interacting protein Apoptosis Mitochondria
This study was supported by the National Natural Science Foundation of China (No. 81371309, Zhaohui He).
ZH and XC designed the project, YL and XC contributed to all experiments and to writing the manuscript. QZ, HZ, DJ, WQ, and LL helped to finish part of the experiments. JZ and XX were mainly responsible for the analysis of data and for writing the manuscript. RD helped to revise the manuscript, especially the language. All authors read and provided their approval for the final version of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors have no conflicts of interest to declare.
All animal experiments were conducted according to a protocol approved by the Animal Ethics and Use Committee of Chongqing Medical University (Permit no. SCXK (Chongqing) 2007–0001).
- 7.Benfica PL, Avila RI, Rodrigues BDS, Cortez AP, Batista AC, Gaeti MPN, Lima EM, Rezende KR, Valadares MC (2017) 4-Nerolidylcatechol: apoptosis by mitochondrial mechanisms with reduction in cyclin D1 at G0/G1 stage of the chronic myelogenous K562 cell line. Pharm Biol 55:1899–1908. https://doi.org/10.1080/13880209.2017.1311351 CrossRefGoogle Scholar
- 8.Nabatchian F, Moradi A, Aghaei M, Ghanadian M, Jafari SM, Tabesh S (2017) New 6(17)-epoxylathyrane diterpene: aellinane from Euphorbia aellenii induces apoptosis via mitochondrial pathway in ovarian cancer cell line. Toxicol Mech Methods 27:622–630. https://doi.org/10.1080/15376516.2017.1347735 CrossRefGoogle Scholar
- 9.Yu K, Wang T, Li Y, Wang C, Wang X, Zhang M, Xie Y, Li S, An Z, Ye T (2017) Niclosamide induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in human thyroid cancer in vitro. Biomed Pharmacother 92:403–411. https://doi.org/10.1016/j.biopha.2017.05.097 CrossRefGoogle Scholar
- 14.Ye X, Zuo D, Yu L, Zhang L, Tang J, Cui C, Bao L, Zan K, Zhang Z, Yang X, Chen H, Tang H, Zu J, Shi H, Cui G (2017) ROS/TXNIP pathway contributes to thrombin induced NLRP3 inflammasome activation and cell apoptosis in microglia. Biochem Biophys Res Commun 485:499–505. https://doi.org/10.1016/j.bbrc.2017.02.019 CrossRefGoogle Scholar
- 16.Wei M, Jiao D, Han D, Wu J, Wei F, Zheng G, Guo Z, Xi W, Yang F, Xie P, Zhang L, Yang AG, Wang H, Qin W, Wen W (2017) Knockdown of RNF2 induces cell cycle arrest and apoptosis in prostate cancer cells through the upregulation of TXNIP. Oncotarget 8:5323–5338. https://doi.org/10.18632/oncotarget.14142 Google Scholar
- 19.Zhao Q, Che X, Zhang H, Fan P, Tan G, Liu L, Jiang D, Zhao J, Xiang X, Liang Y, Sun X, He Z (2017) Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage. J Neuroinflamm 14:104. https://doi.org/10.1186/s12974-017-0878-6 CrossRefGoogle Scholar
- 22.Duris K, Manaenko A, Suzuki H, Rolland WB, Krafft PR, Zhang JH (2011) alpha7 nicotinic acetylcholine receptor agonist PNU-282987 attenuates early brain injury in a perforation model of subarachnoid hemorrhage in rats. Stroke 42:3530–3536. https://doi.org/10.1161/strokeaha.111.619965 CrossRefGoogle Scholar
- 24.Lanzillotta A, Pignataro G, Branca C, Cuomo O, Sarnico I, Benarese M, Annunziato L, Spano P, Pizzi M (2013) Targeted acetylation of NF-kappaB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window. Neurobiol Dis 49:177–189. https://doi.org/10.1016/j.nbd.2012.08.018 CrossRefGoogle Scholar
- 26.Xi G, Hua Y, Keep RF, Younger JG, Hoff JT (2002) Brain edema after intracerebral hemorrhage: the effects of systemic complement depletion. Acta Neurochir Suppl 81:253–256Google Scholar
- 27.Tsubokawa T, Solaroglu I, Yatsushige H, Cahill J, Yata K, Zhang JH (2006) Cathepsin and calpain inhibitor E64d attenuates matrix metalloproteinase-9 activity after focal cerebral ischemia in rats. Stroke 37:1888–1894. https://doi.org/10.1161/01.str.0000227259.15506.24 CrossRefGoogle Scholar
- 32.Yan J, Liu XH, Han MZ, Wang YM, Sun XL, Yu N, Li T, Su B, Chen ZY (2015) Blockage of GSK3beta-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer’s disease. Neurobiol Aging 36:211 – 27 doi. https://doi.org/10.1016/j.neurobiolaging.2014.08.005 Google Scholar
- 34.Nivet-Antoine V, Cottart CH, Lemarechal H, Vamy M, Margaill I, Beaudeux JL, Bonnefont-Rousselot D, Borderie D (2010) trans-Resveratrol downregulates Txnip overexpression occurring during liver ischemia-reperfusion. Biochimie 92:1766–1771. https://doi.org/10.1016/j.biochi.2010.07.018 CrossRefGoogle Scholar
- 36.Bedarida T, Baron S, Vibert F, Ayer A, Henrion D, Thioulouse E, Marchiol C, Beaudeux JL, Cottart CH, Nivet-Antoine V (2016) Resveratrol decreases TXNIP mRNA and protein nuclear expressions with an arterial function improvement in old mice. J Gerontol A 71:720–729. https://doi.org/10.1093/gerona/glv071 CrossRefGoogle Scholar
- 43.Chen Q, Chai YC, Mazumder S, Jiang C, Macklis RM, Chisolm GM, Almasan A (2003) The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. Cell Death Differ 10:323–334. https://doi.org/10.1038/sj.cdd.4401148 CrossRefGoogle Scholar
- 46.Lu J, Holmgren A (2014) The thioredoxin antioxidant system. Free Radic Biol Med 66:75–87. https://doi.org/10.1016/j.freeradbiomed.2013.07.036 CrossRefGoogle Scholar
- 50.Ramus SM, Cilensek I, Petrovic MG, Soucek M, Kruzliak P, Petrovic D (2016) Single nucleotide polymorphisms in the Trx2/TXNIP and TrxR2 genes of the mitochondrial thioredoxin antioxidant system and the risk of diabetic retinopathy in patients with Type 2 diabetes mellitus. J Diabetes Complications 30:192–198. https://doi.org/10.1016/j.jdiacomp.2015.11.021 CrossRefGoogle Scholar