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Expression Profiling of Genes Regulated by Sphingosine Kinase1 Natarajan et al. BMC Genomics (2017) 18:664 DOI 10.1186/s12864-017-4048-0 RESEARCHARTICLE Open Access Expression profiling of genes regulated by sphingosine kinase1 signaling in a murine model of hyperoxia induced neonatal bronchopulmonary dysplasia Viswanathan Natarajan1,2,3, Alison W. Ha1, Yangbasai Dong1, Narsa M. Reddy2, David L. Ebenezer3, Prasad Kanteti2, Sekhar P. Reddy1, J. Usha Raj1, Zhengdeng Lei4, Mark Maienschein-Cline4, Zarema Arbieva5 and Anantha Harijith2,6* Abstract Background: Sphingosine- 1-Phosphate (S1P) is a bioactive lipid and an intracellular as well as an extracellular signaling molecule. S1P ligand specifically binds to five related cell surface G-protein-coupled receptors (S1P1-5). S1P levels are tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and catabolism by S1P phosphatases, lipid phosphate phosphatases and S1P lyase. We previously reported that knock down of SphK1 (Sphk1−/−) in a neonatal mouse BPD model conferred significant protection against hyperoxia induced lung injury. To better understand the underlying molecular mechanisms, genome-wide gene expression profiling was performed on mouse lung tissue using Affymetrix MoGene 2.0 array. Results: Two-way ANOVA analysis was performed and differentially expressed genes under hyperoxia were identified using Sphk1−/− mice and their wild type (WT) equivalents. Pathway (PW) enrichment analyses identified several signaling pathways that are likely toplayakeyroleinhyperoxiainducedlunginjuryinthe neonates. These included signaling pathways that were anticipated such as those involved in lipid signaling, cell cycle regulation, DNA damage/apoptosis, inflammation/immune response, and cell adhesion/extracellular matrix (ECM) remodeling. We noted hyperoxia induced downregulation of the expression of genes related to mitoticspindleformationintheWTwhichwasnotobservedinSphk1−/− neonates. Our data clearly suggests a role for SphK1 in neonatal hyperoxic lung injury through elevated inflammation and apoptosis in lung tissue. Further, validation by RT-PCR on 24 differentially expressed genes showed 83% concordance both in terms of fold change and vectorial changes. Our findings are in agreement with previously reported human BPD microarray data and completely support our published in vivo findings. In addition, the data also revealed a significant role for additional unanticipitated signaling pathways involving Wnt and GADD45. Conclusion: Using SphK1 knockout mice and differential gene expression analysis, we have shown here that S1P/SphK1 signaling plays a key role in promoting hyperoxia induced DNA damage, inflammation, apoptosis and ECM remodeling in neonatal lungs. It also appears to suppress pro-survival cellular responses involved in normal lung development. We therefore propose SphK1 as a therapeutic target for the development drugs to combat BPD. Keywords: Sphingosine kinase 1, Sphingosine 1 phosphate, Oxidative stress, Lipid signaling, Neonatal lung injury * Correspondence: [email protected] 2Department of Pharmacology, University of Illinois, Chicago, IL 60612, USA 6Department of Pediatrics, University of Illinois, Room # 3140, COMRB Building, 909, South Wolcott Avenue, Chicago, IL 60612, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Natarajan et al. BMC Genomics (2017) 18:664 Page 2 of 16 Background results suggest that SphK1/S1P signaling cascade medi- Bronchopulmonary dysplasia (BPD) is a chronic condi- ates hyperoxia-induced lung injury by modulation of tion affecting up to 25% of extreme preterm newborn in- genes related to inflammation, apoptosis, immune re- fants [1, 2]. It is characterized by alveolar simplification, sponses and redox signaling in mouse lung. Our data leading to loss of gas exchange area and a decline in also identifies SphK1 as a potential therapeutic target to lung function that worsens with age [3]. Advances in the combat BPD. care of preterm newborn such as ventilation support has increased the survival rates, however, the practice has Methods also elevated the prevalence of BPD [1]. Though BPD is Mouse model of multifactorial in origin, exposure to hyperoxia is one Mouse experiments and animal care of the major contributing factors [4, 5]. There is a pre- All experiments using animals were approved by the ponderance of evidence in support of a role for reactive Institutional Animal Care and Use Committee at the oxygen species (ROS) induced lung injury in the University of Illinois at Chicago (protocol # 15-240). development of BPD [6]. We used male neonatal mice to study the effect of S1P is a signaling bioactive lipid mediator, generated hyperoxiainthenewborndevelopinglungs.Thelung by phosphorylation of sphingosine catalyzed by two development in the neonatal mice at birth is in the intracellular sphingosine kinases (SphKs) 1 & 2. S1P is late canalicular/early alveolar stage corresponding to transported outside the cell either by ATP binding that of a preterm human neonate at 24-26 weeks of − − cassette (ABC) or Spns2 transporter where it exerts its gestation. Sphk1 / mice were obtained from Dr. effects through five types of cell surface G-protein- Richard L. Proia (NIDDK, National Institutes of coupled S1P receptors 1-5 (S1PR1-5). The pleotropic Health, Bethesda), and backcrossed to C57BL/6 back- effects of S1P depend on the pathophysiology and the ground for two generations (F2 hybrid). The resultant type of S1P receptor it binds to [7]. S1P is protective in mixed background of C57BL/6 strain and the original the sepsis model whereas it plays a detrimental role in background (F2 hybrid) was used as controls and is hyperoxic lung injury and asthma [8]. In lung patholo- referred to hereafter as Wild Type (WT). The WT or − − gies such as asthma [8], pulmonary fibrosis [9] and Sphk1 / newborn (NB) mice along with the lactating pulmonary hypertension [10, 11], genetic deletion of dams were exposed to hyperoxia of 75% O2 or normoxia Sphk1 or inhibition of SphK1 activity with small mo- from postnatal (PN) day 1 for 7 days as previously de- lecule inhibitors conferred significant protection from scribed [13]. NB mice (along with their mothers) were airway/lung inflammation and injury. However, in placed in cages in an airtight Plexiglas chamber sepsis-induced lung injury, infusion of S1P protected the (55 × 40 × 50 cm), maintained in hyperoxic condition. animals from lung injury and pulmonary edema by en- Two lactating dams were used. Mothers were alternated hancing endothelial barrier function [12]. Thus, S1P is a between hyperoxia and normoxia every 24 h. The litter double edged sword as its action varies depending upon size was kept limited to 6 pups to control the effects of lit- the agent inducing lung injury or the receptor through ter size on nutrition and growth. The animals were main- which it acts. tained as per the University of Illinois protocol for animal In our neonatal mouse model of BPD, we showed that use. Oxygen levels were constantly monitored by an oxy- hyperoxia increased the expression of SphK1, but not gen sensor that was connected to a relay switch incorpo- SphK2, leading to increased synthesis of S1P [13]. Dele- rated into the oxygen supply circuit. The inside of the tion of Sphk1, but not Sphk2 gene resulted in decreased chamber was kept at atmospheric pressure. The animals S1P levels in lungs accompanied by reduced expression of were sacrificed and the lung tissues collected, homoge- NADPH oxidase (Nox) 2 & 4 and ROS, leading to nized and whole cell lysates prepared for further analysis, amelioration of hyperoxia-induced lung injury. The role of RNA isolation (superior lobe of right lung), and micro- SphK1/S1P on the expression of genes involved in lung in- array studies. flammation, injury and repair is not clear. We therefore hypothesized that reduced inflammation and improved Sample processing and microarray based gene expression − − alveolarization observed in Sphk1 / mice resulted from analyses differential regulation of genes, promoting normal course We used MoGene 2.0 array (Thermo Fisher Scientific, of lung development while suppressing injury. Waltham, MA) that interrogates over 35 thousand To test this hypothesis and to identify the various mouse specific RefSeq transcripts and represents a − − mechanisms by which the Sphk1 / confers pulmonary comprehensive platform for the whole transcriptome ex- protection, differential gene expression analysis in the pression profiling [14]. − − lungs of Sphk1 / mice before and after treatment with Lung tissue was perfused with PBS prior to harvesting hyperoxia was compared to the Wild Type mice. The from the animal, and processed immediately after Natarajan et al. BMC Genomics (2017) 18:664 Page 3 of 16 harvesting. Total RNA was isolated from the whole lung Pathway enrichment analyses and data visualization tissue using microRNeasy® kit (Qiagen, Maryland, Cat We performed pathway enrichment analyses
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