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Gene Expression Profiles of Patients with Cerebral Hematoma Following Spontaneous Intracerebral Hemorrhage

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Gene Expression Profiles of Patients with Cerebral Hematoma Following Spontaneous Intracerebral Hemorrhage MOLECULAR MEDICINE REPORTS 10: 1671-1678, 2014 Gene expression profiles of patients with cerebral hematoma following spontaneous intracerebral hemorrhage TAO YANG1,2, JIANWEN GU1, BIN KONG1,2, YONGQIN KUANG1, LIN CHENG1, JINGMIN CHENG1,2, XUN XIA1,2, YUAN MA1,2 and JUNHAI ZHANG1 1Department of Neurosurgery, Chengdu Military General Hospital, Chengdu, Sichuan 610083; 2Department of Postgraduate, Third Military Medical University, Chongqing 400038, P.R. China Received October 13, 2013; Accepted March 27, 2014 DOI: 10.3892/mmr.2014.2421 Abstract. The present study aimed to investigate the gene ITPR1-RYR2, CAMK2A-RYR2 and ITGA5-LAMB1 interac- functions and expression profiles in perihematomal (PH) tion pairs. The present study provides several potential targets brain regions following spontaneous intracerebral hemor- to decrease hematoma expansion and alleviate neuronal cell rhage. The gene expression profiles were downloaded from death following spontaneous intracerebral hemorrhage. the Gene Expression Omnibus database under accession number GSE24265, which includes 11 brain samples from Introduction different regions, including four samples from PH areas, four from contralateral grey matter (CG) and three from contra- Spontaneous intracerebral hemorrhage (ICH) involves the lateral white matter (CW). The gene expression profiles were extravasation of blood within the brain parenchyma in the pre-processed and the differentially expressed genes (DEGs) absence of trauma or surgery, accounting for 10-30% of all between PH and CG tissue, and PH and CW tissue were identi- strokes worldwide (1). ICH is a complex, dynamic process fied using R packages. The expression of genes in different that consists of three distinct phases (2): i) Initial hemorrhage, tissues was analyzed by hierarchical clustering. Then, the retraction of the clot begins in the first few hours following interaction network between the DEGs was constructed using ICH. ii) Hematoma expansion, hematoma expansion occurs String software. Finally, Gene Ontology was performed and 24 or 48 h following the initial onset of symptoms, which pathway analysis was conducted using FuncAssociate and involves a sudden increase in intracranial pressure, disrupting Expression Analysis Systematic Explorer to identify the gene the integrity of the local tissue and blood-brain barrier. In function. As a result, 399 DEGs were obtained between PH addition, obstructed venous outflow promotes the activation and CG, and 756 DEGs were identified between PH and CW. of tissue thromboplastin, resulting in local coagulopathy. There were 35 common DEGs between the two groups. These (iii) Perihematoma (PH) edema, PH cerebral edema develops DEGs may be involved in PH edema by regulating the calcium within the first few days following ICH as a result of an signaling pathway [calcium channel, voltage-dependent, inflammatory response [activation of cellular (leukocytes, T-type, α1I subunit, Ca2+/calmodulin-dependent protein macrophages and microglia) and molecular (cytokines, prote- kinase II α (CAMK2A), ryanodine receptor 2 (RYR2) and ases and reactive oxygen species) components] (3) secondary inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1)], cell to local release of thrombin and other end products of coagula- proliferation (sphingosine kinase 1), neuron differentiation tion from the hematoma, and also due to cytotoxic mediators (Ephrin-A5) or extracellular matrix-receptor interaction (hemoglobin and its degradation products, heme and iron) that [collagen, type I, α 2, laminin B1 (LAMB1), syndecan 2, are released from red blood cells (4-6). fibronectin 1 and integrin α5 (ITGA5)]. A number of genes The hematoma expansion rate and PH edema volume are may cooperate to participate in the same pathway, such as key factors to predict neurological deterioration and survival. Hematoma volume >30 ml is associated with increased mortality (7). When the hemorrhagic volume exceeds 150 ml, cerebral perfusion pressure falls to zero, which subsequently leads to patient mortality (8). Therefore, prevention of hema- Correspondence to: Dr Jianwen Gu, Department of Neurosurgery, Chengdu Military General Hospital, 270 Toanhui Road, Chengdu, toma expansion is a logical therapeutic target (9). Additionally, Sichuan 610083, P.R. China it is possible that anti-inflammatory and anti-apoptotic drugs E-mail: [email protected] may have the therapeutic potential to ameliorate secondary brain injury following ICH. For example, sesamin confers Key words: spontaneous intracerebral hemorrhage, perihematomal neuroprotection in rat ICH by suppressing activation of tissue, differentially expressed gene, interaction network, function microglia and the p44/42 MAPK pathway (10). Ginkgolide B and pathway enrichment analysis was able to significantly suppress the gene expression of Toll-like receptor 4 and nuclear factor-κB, reduce the concen- trations of tumor necrosis factor-α, interleukin (IL)-1β and 1672 YANG et al: GENE EXPRESSION PROFILES OF CEREBRAL HEMATOMA IL-6 as well as reduce the number of apoptotic neuronal cells Table I. Demographic and tissue sampling data. in hemorrhagic rat brain tissues (11). Recently, Carmichael et al (12) attempted to investigate the Case Sex Age Time S-E Time E-T PH CG CW gene expression pattern in PH tissues of ICH rat models in a 27 F 72 12 h 5 h 1 1 1 microarray study, which simultaneously measured transcript 28 F 95 39 h 2.5 h 1 1 1 abundances of thousands of genes in a cell population or 30 M 67 17 h 3 h 1 1 tissue. The results indicated a robust upregulation of pro-/anti- 31 M 86 4 days 4 h 1 1 1 inflammatory networks and a downregulation of neuronal signaling pathways (12). Furthermore, Rosell et al (13) investi- F, female; M, male; S-E, stroke to exitus; E-T, exitus to tissue samples; gated the genomic profile following spontaneous human ICH PH, perihematomal areas; CG, contralateral grey matter; CW, contralat- and suggested that the significantly overexpressed genes in eral white matter. the PH areas encoded for cytokines, chemokines, coagulation, cell growth and proliferation factors, while the downregulated genes encoded proteins involved in the cell cycle or neuro- trophins. Therefore, the identified genes may be potential different. The genes were clustered based on their expression targets for ICH therapy. in two groups using Cluster analysis (18). The expression The present study aimed to further identify the differen- differences in the various tissues were visualized by heatmap tially expressed genes (DEGs) between PH and contralateral (Clifton Watt, Stanford University, USA). healthy tissues [grey (CG) matter and white (CW) matter] using a different statistical approach and threshold. Further Construction of the interaction network. Numerous activi- interaction network and function analyses were also performed ties in the body, including important physiological activities for these DEGs. It is expected that these data may further and responses to the external or internal environment, are elucidate the processes and mechanisms of death caused by performed by the binding and dissociation of proteins. All hematoma following spontaneous ICH. of these activities are conducted by signaling transduction networks consisting of protein-protein interactions (19). Materials and methods Therefore, detailed investigations into protein interac- tion networks is essential for the understanding of bodily Microarray data. The gene expression profiles were down- systems (20). Based on the sequence and structure informa- loaded from the Gene Expression Omnibus under accession tion of DEGs, their interaction possibility was predicted number GSE24265 (13), which includes 11 brain samples from according to the String database (http://string.embl.de/) that different regions of four deceased patients who had suffered quantitatively integrates interaction data from four sources from a supratentorial ICH within four days prior to mortality. [genomic context, high-throughput experiments, (conserved) Of these samples, four were from PH tissues, four from CG co-expression and previous knowledge] for a large number of and three from CW. The study group included two female organisms, and transfers information between these organ- and two male subjects with a median age of 79 years (range, isms where applicable (21). Furthermore, the interaction 68-92 years). The samples from PH, CG and CW tissue were network was also constructed for the two groups; PH vs. CG obtained within the first 5 h following mortality, snap frozen and PH vs. CW. in liquid nitrogen and stored at -80˚C until RNA isolation. The original studies by Rosell et al (13) was approved by the Ethics Functional enrichment of DEGs in interaction networks. Committee of the Vall d'Hebron Hospital (Barcelona, Spain) The annotation was performed for the genes in protein inter- and informed and written consent was acquired from all of action networks. FuncAssociate (http://llama.med.harvard. the patients or patient's relatives. Demographic and tissue edu/funcassociate) is a web application that identifies proper- sampling data are presented in Table I. The array platform was ties enriched in lists of genes or proteins that emerge from GPL570 [Human Genome U133 Plus 2.0 Array (Affymetrix large-scale experimentation (22). The interactive DEGs were Inc., Santa Clara, CA, USA)]. The array annotation informa- screened and functional enrichment analysis was performed tion was from Affymatrix, including the information for all using FuncAssociate (22).
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