The online version of this article (https://doi.org/10.1007/s12028-019-00861-x) contains supplementary material, which is available to authorized users.
Huichun Xu and Boryana Stamova are equal contributors to this study.
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Though there are many biomarker studies of plasma and serum in patients with aneurysmal subarachnoid hemorrhage (SAH), few have examined blood cells that might contribute to vasospasm. In this study, we evaluated inflammatory and prothrombotic pathways by examining mRNA expression in whole blood of SAH patients with and without vasospasm.
Adult SAH patients with vasospasm (n = 29) and without vasospasm (n = 21) were matched for sex, race/ethnicity, and aneurysm treatment method. Diagnosis of vasospasm was made by angiography. mRNA expression was measured by Affymetrix Human Exon 1.0 ST Arrays. SAH patients with vasospasm were compared to those without vasospasm by ANCOVA to identify differential gene, exon, and alternatively spliced transcript expression. Analyses were adjusted for age, batch, and time of blood draw after SAH.
At the gene level, there were 259 differentially expressed genes between SAH patients with vasospasm compared to patients without (false discovery rate < 0.05, |fold change| ≥ 1.2). At the exon level, 1210 exons representing 1093 genes were differentially regulated between the two groups (P < 0.005, ≥ 1.2 |fold change|). Principal components analysis segregated SAH patients with and without vasospasm. Signaling pathways for the 1093 vasospasm-related genes included adrenergic, P2Y, ET-1, NO, sildenafil, renin–angiotensin, thrombin, CCR3, CXCR4, MIF, fMLP, PKA, PKC, CRH, PPARα/RXRα, and calcium. Genes predicted to be alternatively spliced included IL23A, RSU1, PAQR6, and TRIP6.
This is the first study to demonstrate that mRNA expression in whole blood distinguishes SAH patients with vasospasm from those without vasospasm and supports a role of coagulation and immune systems in vasospasm.
Lantigua H, Ortega-Gutierrez S, Schmidt JM, et al. Subarachnoid hemorrhage: who dies, and why? Crit Care. 2015;19:309. CrossRef
Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43:1711–37. CrossRef
de Oliveira Manoel AL, Macdonald RL. Neuroinflammation as a Target for Intervention in Subarachnoid Hemorrhage. Front Neurol. 2018;9:292. CrossRef
McBride DW, Blackburn SL, Peeyush KT, Matsumura K, Zhang JH. The role of thromboinflammation in delayed cerebral ischemia after subarachnoid hemorrhage. Front Neurol. 2017;8:555. CrossRef
Hong CM, Tosun C, Kurland DB, Gerzanich V, Schreibman D, Simard JM. Biomarkers as outcome predictors in subarachnoid hemorrhage—a systematic review. Biomarkers. 2014;19:95–108. CrossRef
Burrell C, Avalon NE, Siegel J, et al. Precision medicine of aneurysmal subarachnoid hemorrhage, vasospasm and delayed cerebral ischemia. Expert Rev Neurother. 2016;16:1251–62. CrossRef
Stamova B, Ander BP, Jickling G, et al. The intracerebral hemorrhage blood transcriptome in humans differs from the ischemic stroke and vascular risk factor control blood transcriptomes. J Cereb Blood Flow Metab 2018 Apr 13:271678X18769513.
Durocher M, Ander BP, Jickling G, et al. Co-expression modules and hub genes that drive the peripheral immune response to human intracerebral hemorrhage. J Neuroinflammation. 2019;16(1):56. CrossRef
Pera J, Korostynski M, Golda S, et al. Gene expression profiling of blood in ruptured intracranial aneurysms: in search of biomarkers. J Cereb Blood Flow Metab. 2013;33:1025–31. CrossRef
Roder C, Kasuya H, Harati A, Tatagiba M, Inoue I, Krischek B. Meta-analysis of microarray gene expression studies on intracranial aneurysms. Neuroscience. 2012;201:105–13. CrossRef
Osteraas ND, Lee VH. Neurocardiology. Handb Clin Neurol. 2017;140:49–65. CrossRef
Fujiwara M, Tsukahara T, Taniguchi T. Alpha-adrenoceptors in human and animal cerebral arteries: alterations after sympathetic denervation and subarachnoid hemorrhage. Trends Pharmacol Sci. 1989;10:329–32. CrossRef
Pappas AC, Koide M, Wellman GC. Purinergic signaling triggers endfoot high-amplitude Ca 2+ signals and causes inversion of neurovascular coupling after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2016;36:1901–12. CrossRef
Laban KG, Vergouwen MD, Dijkhuizen RM, et al. Effect of endothelin receptor antagonists on clinically relevant outcomes after experimental subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2015;35:1085–9. CrossRef
Vanhoutte PM. Nitric oxide: from good to bad. Ann Vasc Dis. 2018;11:41–51. CrossRef
Guo ZN, Shao A, Tong LS, Sun W, Liu J, Yang Y. The role of nitric oxide and sympathetic control in cerebral autoregulation in the setting of subarachnoid hemorrhage and traumatic brain injury. Mol Neurobiol. 2016;53:3606–15. CrossRef
Dhar R, Washington C, Diringer M, et al. Acute effect of intravenous sildenafil on cerebral blood flow in patients with vasospasm after subarachnoid hemorrhage. Neurocrit Care. 2016;25:201–4. CrossRef
Washington CW, Derdeyn CP, Dhar R, et al. A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage. J Neurosurg. 2016;124:318–27. CrossRef
Lo BW, Fukuda H, Nishimura Y, et al. Pathophysiologic mechanisms of brain-body associations in ruptured brain aneurysms: a systematic review. Surg Neurol Int. 2015;6:136. CrossRef
Griessenauer CJ, Tubbs RS, Foreman PM, et al. Association of renin-angiotensin system genetic polymorphisms and aneurysmal subarachnoid hemorrhage. J Neurosurg. 2018;128:86–93. CrossRef
Hirano K, Hirano M. Current perspective on the role of the thrombin receptor in cerebral vasospasm after subarachnoid hemorrhage. J Pharmacol Sci. 2010;114:127–33. CrossRef
Hollenberg MD. Novel insights into the delayed vasospasm following subarachnoid haemorrhage: importance of proteinase signalling. Br J Pharmacol. 2012;165:103–5. CrossRef
Li T, Zhang P, Yuan B, Zhao D, Chen Y, Zhang X. Thrombin-induced TGF-beta1 pathway: a cause of communicating hydrocephalus post subarachnoid hemorrhage. Int J Mol Med. 2013;31:660–6. CrossRef
Chen YH, Cheng ZY, Shao LH, Shentu HS, Fu B. Macrophage migration inhibitory factor as a serum prognostic marker in patients with aneurysmal subarachnoid hemorrhage. Clin Chim Acta. 2017;473:60–4. CrossRef
Liu YC, Tsai YH, Tang SC, et al. Cytokine MIF enhances blood-brain barrier permeability: impact for therapy in ischemic stroke. Sci Rep. 2018;8:743. CrossRef
Inacio AR, Ruscher K, Leng L, Bucala R, Deierborg T. Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke. J Cereb Blood Flow Metab. 2011;31:1093–106. CrossRef
Turtzo LC, Li J, Persky R, et al. Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice. Neurobiol Dis. 2013;54:421–31. CrossRef
Lacy M, Kontos C, Brandhofer M, et al. Identification of an Arg-Leu-Arg tripeptide that contributes to the binding interface between the cytokine MIF and the chemokine receptor CXCR28. Sci Rep. 2018;8:5171. CrossRef
Zhao S, Qu H, Zhao Y, et al. CXCR29 antagonist AMD3100 reverses the neurogenesis and behavioral recovery promoted by forced limb-use in stroke rats. Restor Neurol Neurosci. 2015;33:809–21. PubMed
Luo J, Hu X, Zhang L, et al. Physical exercise regulates neural stem cells proliferation and migration via SDF-1alpha/CXCR30 pathway in rats after ischemic stroke. Neurosci Lett. 2014;578:203–8. CrossRef
Bach HHT, Wong YM, Tripathi A, et al. Chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3 regulate vascular alpha(1)-adrenergic receptor function. Mol Med. 2014;20:435–47. CrossRef
Maugeri N, Manfredi AA, Maseri A. Clinical and experimental evidences on the prothrombotic properties of neutrophils. Srp Arh Celok Lek. 2010;138(Suppl 1):50–2. CrossRef
Geddings JE, Mackman N. New players in haemostasis and thrombosis. Thromb Haemost. 2014;111:570–4. CrossRef
Jickling GC, Liu D, Ander BP, Stamova B, Zhan X, Sharp FR. Targeting neutrophils in ischemic stroke: translational insights from experimental studies. J Cereb Blood Flow Metab. 2015;35:888–901. CrossRef
Raya AK, Diringer MN. Treatment of subarachnoid hemorrhage. Crit Care Clin. 2014;30:719–33. CrossRef
Wada K, Osuka K, Watanabe Y, et al. Subarachnoid hemorrhage induces neuronal nitric oxide synthase phosphorylation at Ser(1412) in the dentate gyrus of the rat brain. Nitric Oxide: Biol Chem. 2017;81:67–74. CrossRef
Sun L, Zhang W, Wang X, Song J, Li M. Inhibition of protein kinase C signal reduces ET receptor expression and basilar vasospasm after subarachnoid hemorrhage in rats. J Integr Neurosci. 2012;11:439–51. CrossRef
Hasan DM, Starke RM, Gu H, et al. Smooth muscle peroxisome Proliferator-activated receptor gamma plays a critical role in formation and rupture of cerebral aneurysms in mice in vivo. Hypertension. 2015;66:211–20. CrossRef
Chang CZ, Wu SC, Kwan AL. Glycyrrhizin attenuates proinflammatory cytokines through a peroxisome proliferator-activated receptor-gamma-dependent mechanism and experimental vasospasm in a rat model. J Vasc Res. 2015;52:12–21. CrossRef
Wu Y, Zhao XD, Zhuang Z, et al. Peroxisome proliferator-activated receptor gamma agonist rosiglitazone attenuates oxyhemoglobin-induced Toll-like receptor 4 expression in vascular smooth muscle cells. Brain Res. 2010;1322:102–8. CrossRef
Koskimaki J, Matsui N, Umemori J, Rantamaki T, Castren E. Nimodipine activates TrkB neurotrophin receptors and induces neuroplastic and neuroprotective signaling events in the mouse hippocampus and prefrontal cortex. Cell Mol Neurobiol. 2015;35:189–96. CrossRef
Lv O, Zhou F, Zheng Y, Li Q, Wang J, Zhu Y. Mild hypothermia protects against early brain injury in rats following subarachnoid hemorrhage via the TrkB/ERK/CREB signaling pathway. Mol Med Rep. 2016;14:3901–7. CrossRef
Fujii M, Sherchan P, Soejima Y, et al. Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB-Bcl-2 pathway after subarachnoid hemorrhage in rats. Exp Neurol. 2014;261:396–403. CrossRef
Su J, Tongzhou E, Guo Q, Lei Y, Gu Y. Memory deficits after aneurysmal subarachnoid hemorrhage: a functional magnetic resonance imaging study. World Neurosurg. 2018;111:e500–6. CrossRef
Egeto P, Loch Macdonald R, Ornstein TJ, Schweizer TA. Neuropsychological function after endovascular and neurosurgical treatment of subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2018;128:768–76. CrossRef
Provencio JJ, Swank V, Lu H, et al. Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors. Brain Behav Immun. 2016;54:233–42. CrossRef
- mRNA Expression Profiles from Whole Blood Associated with Vasospasm in Patients with Subarachnoid Hemorrhage
Bradley P. Ander
Glen C. Jickling
Frank R. Sharp
Nerissa U. Ko
- Springer US
Print ISSN: 1541-6933
Elektronische ISSN: 1556-0961
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