Biology Computes | Genomics and bioinformatics at Georgia …
BIOL 6150 – Genomics and Applied BioinformaticsGroup Project: Microarray AnalysisTitle: Identification of the Shear-and Side-specific genes relatedto Aortic Valve CalcificationGroup: Swetha Rathan, HaozhengTian, Sandra Baethke, WafaEldarratBackground:Aortic valve (AV) calcification is one of the major causes of morbidity and mortality in elderly population ADDIN EN.CITE <EndNote><Cite><Author>Rajamannan</Author><Year>2007</Year><RecNum>164</RecNum><DisplayText>[1, 2]</DisplayText><record><rec-number>164</rec-number><foreign-keys><key app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">164</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rajamannan, Nalini M.</author><author>Bonow, Robert O.</author><author>Rahimtoola, Shahbudin H.</author></authors></contributors><titles><title>Calcific aortic stenosis: an update</title><secondary-title>Nat Clin Pract Cardiovasc Med</secondary-title></titles><periodical><full-title>Nat Clin Pract Cardiovasc Med</full-title></periodical><pages>254-262</pages><volume>4</volume><number>5</number><dates><year>2007</year></dates><publisher>Nature Publishing Group</publisher><isbn>1743-4297</isbn><work-type>10.1038/ncpcardio0827</work-type><urls><related-urls><url> app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Otto, Catherine M.</author><author>Lind, Bonnie K.</author><author>Kitzman, Dalane W.</author><author>Gersh, Bernard J.</author><author>Siscovick, David S.</author><author>The Cardiovascular Health, Study</author></authors></contributors><titles><title>Association of Aortic-Valve Sclerosis with Cardiovascular Mortality and Morbidity in the Elderly</title><secondary-title>N Engl J Med</secondary-title></titles><pages>142-147</pages><volume>341</volume><number>3</number><dates><year>1999</year><pub-dates><date>July 15, 1999</date></pub-dates></dates><urls><related-urls><url>;[1, 2]. The primary risk factors for AV calcification include hypertension, congenital defects like bicuspid AV, age, smoking, diabetes and chronic kidney diseasePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV3YXJ0PC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48
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ADDIN EN.CITE.DATA [3, 4]. The AV experiences dynamic mechanical environment with significant variations in pressure, bending and shear on either side ADDIN EN.CITE <EndNote><Cite><Author>Thubrikar</Author><Year>1990</Year><RecNum>77</RecNum><DisplayText>[5]</DisplayText><record><rec-number>77</rec-number><foreign-keys><key app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">77</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Thubrikar, Mano.</author></authors></contributors><titles><title>The aortic valve</title></titles><keywords><keyword>Aortic valve.</keyword></keywords><dates><year>1990</year></dates><pub-location>Boca Raton, Fla. :</pub-location><publisher>CRC Press</publisher><isbn>0849347718</isbn><call-num>QP114.A57 T48 1990</call-num><urls></urls><language>Array</language></record></Cite></EndNote>[5]. Under physiological conditions, these stimuli constantly renew and remodel the valve. Any alterations to this mechanical environment have been shown to cause a disease condition, eventually resulting in aortic stenosis (AS) and aortic regurgitation (AR) ADDIN EN.CITE <EndNote><Cite><Author>Miller</Author><Year>2011</Year><RecNum>153</RecNum><DisplayText>[6]</DisplayText><record><rec-number>153</rec-number><foreign-keys><key app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">153</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Miller, Jordan D.</author><author>Weiss, Robert M.</author><author>Heistad, Donald D.</author></authors></contributors><titles><title>Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms</title><secondary-title>Circulation Research</secondary-title></titles><periodical><full-title>Circulation Research</full-title></periodical><pages>1392-1412</pages><volume>108</volume><number>11</number><dates><year>2011</year><pub-dates><date>May 27, 2011</date></pub-dates></dates><urls><related-urls><url>;[6]. Several studies have been done to characterize the role of shear stresses on vascular biology and have indicated that low and oscillatory shear stress is atheroprone whereas high shear is atheroprotectivePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWNvc2t5PC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA [7-10]. It has been speculated that the reduced shear stresses on the non-coronary leaflet of the AV due to the lack of coronary flow are responsible for the increased susceptibility to calcification of that leaflet ADDIN EN.CITE <EndNote><Cite><Author>Hsu</Author><Year>2005</Year><RecNum>201</RecNum><DisplayText>[11]</DisplayText><record><rec-number>201</rec-number><foreign-keys><key app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">201</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hsu, S. Y.</author><author>Hsieh, I. C.</author><author>Chang, S. H.</author><author>Wen, M. S.</author><author>Hung, K. C.</author></authors></contributors><titles><title>Aortic valve sclerosis is an echocardiographic indicator of significant coronary disease in patients undergoing diagnostic coronary angiography</title><secondary-title>International Journal of Clinical Practice</secondary-title></titles><periodical><full-title>International Journal of Clinical Practice</full-title></periodical><pages>72-77</pages><volume>59</volume><number>1</number><dates><year>2005</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1368-5031</isbn><accession-num>WOS:000226938200015</accession-num><urls><related-urls><url><Go to ISI>://WOS:000226938200015</url></related-urls></urls><electronic-resource-num>10.1111/j.1742-1241.2004.00219.x</electronic-resource-num></record></Cite></EndNote>[11]. Hypothesis: Adverse patterns of shear stress were found to upregulate inflammatory markers in valve leaflet tissues, indicating that the fibrosa is more atheroprone compared to the ventricularis side, which is also seen in calcified human valves.Thus the hypothesis of our study is that the Human Aortic Valve Endothelial Cells of fibrosa side (fHAVECs) when exposed to oscillatory shear stress expresses similar genes that are seen in the calcified human AVs. Data sets chosen:For our comparison purposes, we have chosen two data sets as follows:GSE26953 (4 data sets - 6 replicates per data set) ADDIN EN.CITE <EndNote><Cite><Author>Holliday</Author><Year>2011</Year><RecNum>129</RecNum><DisplayText>[12]</DisplayText><record><rec-number>129</rec-number><foreign-keys><key app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Holliday, Casey J.</author><author>Ankeny, Randall F.</author><author>Jo, Hanjoong</author><author>Nerem, Robert M.</author></authors></contributors><titles><title>Discovery of Shear- and Side-specific mRNAs and miRNAs in Human Aortic Valvular Endothelial Cells</title><secondary-title>American Journal of Physiology - Heart and Circulatory Physiology</secondary-title></titles><dates><year>2011</year><pub-dates><date>June 24, 2011</date></pub-dates></dates><urls><related-urls><url>;[12]This is the data was extracted from part of the study: Discovery of Shear- and Side-specific mRNAs and miRNAs in Human Aortic Valvular Endothelial Cells. In this study the HAVECs from either sides of the valve were exposed to different shear stresses (both atheroprotective and atheroprone). The total RNA was collected and the miRNA and mRNA arrays were carried out to identify if there are any differentially expressed shear and side specific miRNA and mRNA that could play a role in AV disease progression. For our project purposes, we used only the mRNA data sets. mRNA microarray data was available for different data sets such asfHAVEC exposed to OS (FO)vHAVEC exposed to OS (VO)fHAVEC exposed to LS (FL)vHAVEC exposed to LS (VL)Where the HAVECs are the human aortic valve endothelial cells from either the fibrosa side or the ventricularis side (fHAVECs or vHAVECs respectively). OS: Oscillatory shear stress( pro-atherogenic) and LS : Laminar shear ( atheroprotective). GSE12644 ( 2 data sets – with 3 or 4 replicates)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3NzZTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [13]This data set has been extracted from the study: Gene expression profile of normal and calcified stenotic human aortic valves. This study was used to gene expression profiling of human aortic valves in patients with or without aortic stenosis. The dataset was generated constituteda large-scale quantitative measurements of gene expression in normal and stenotic human valves. The goal of this study was to compare gene expression levels between the two groups and identified a list of genes that are up-or down-regulated in aortic stenosis. For our project purposes we used the entire mRNA microarray data set provided, which is the followingHuman Aortic Valve – control (10 samples)Human Calcified Aortic Valve (diseased) - (10 samples)Objectives: In this project, the first step was to do the microarray analysis and to identify the differentially expressed genes within each data set. Our comparison groups areFor the sheared HAVECs data set, we have the following groupsOverall differences between different shear stress : Oscillatory vs LaminarOverall differences between the sides : Fibrosa and VentricularisFor more specific comparisons, we did the following. fHAVECsvsvHAVECs exposed to same shear stress – OscillatoryfHAVECsvsvHAVECs exposed to same shear stress – LaminarfHAVECs exposed to different shear stresses – Oscillatory vs Laminar vHAVECs exposed to different shear stresses – Oscillatory vs LaminarFor the calcified and normal AV microarray data set, we compared the gene expression profiles between normal and calcified human AVs. From 1, Our comparisons a and b gives us the list of the differentially expressed genes that are shear sensitive and side- dependent respectively. Comparisons c and d will give us the differentially expressed genes that are side-dependent when exposed to same shear. Comparisons e and f will give us the differentially expressed genes that are shear-dependent on the same side. From 2, We will obtain the gene expression profiles that are expressed in diseased calcified genes. In our further steps, we will retrieve all the genes from the ids of the array platforms and then separately run the statistics to see if any of the shear conditions upregulate the gene expressions that are related to AV calcification. Project detailed steps:We used the tutorial provided and followed all the steps in order to retrieve the data sets from the GEO website. Briefly, we use the accession number of the paper with shear data, GSE26953, and obtained the information of the experimental design. : 24 samples; n=6 for the following 4 groups: FO, VO, FL, and VL (24 miRNA and 24 mRNA arrays. We have downloaded the series matrix files in txt.gz format. Since gz format files are all zipped files, use the 7 zip or any other unzipping program to extract files. We then formatted it according to the specifications for the JMP genomics software, as provided in the tutorial. Original, formatted and normalized data files attached: The data files were formatted, standardized and used for further analysis. Following are the list of files in the order of entire expression data, experimental design and normalized data for two accession numbers. These files are also attached along with the differentially expression profile files. GSE 12644 – Calcified vs. Normal human aortic valvesgse12644_disease_expgse12644_disease_expression_datagse12644_disease_expression_stdGSE 26953 – Shear datagse26953_shear_expgse26953_shear_gene_express_stdgse26953_shear_gene_expressionIdentification of differentially expressed genes:To identify the differentially expressed genes, we followed the instructions in the tutorial, and used the pFDR – multiple testing method, one-way ANOVA for overall statistics, and t-test for individual pairs. Alpha: 0.05. All the specific p-values, corresponding list and the file names are listed in the table as follows. Also specifically the list of these genes were obtained by selecting only the genes that are expressed above the threshold p-value (above the red line in the anova plots). Overall differences between different shear stress : Oscillatory vs Laminar : Effect of shear stress Overall differences between the sides : Fibrosa and Ventricularis – overall side specificityfHAVECsvsvHAVECs exposed to same shear stress – Oscillatory – Effect of oscillatory or pro-atherogenic on either sides. fHAVECsvsvHAVECs exposed to same shear stress – Laminar – Effect of laminar or atheroprotective shear on either sides.fHAVECs exposed to different shear stresses – Oscillatory vs Laminar – Response of fibrosa side to different shear stresses – pathological vs physiological shear stresses. vHAVECs exposed to different shear stresses – Oscillatory vs Laminar - Response of fibrosa side to different shear stresses – pathological vs physiological shear stressesFixed effect: calcified VS normal. Cell type: aortic valve – To identify the differentially expressed genes in pathological conditions. Parameter Table: Each row in this table details the contents of each file. See individual files in attachment for row level details.Serial NoGroup-log10(p-value)cuttoffDifferentially expressed genesFold Change(See individual files)File name attached1Overall differences between different shear stress : Oscillatory vs Laminar2.571929DIFF Column details the FOLD CHANGE for the corresponding row for each genegse26953_between shear all sides diff expressed2Overall differences between the sides : Fibrosa and Ventricularis2.5611DIFF Column details the FOLD CHANGE for the corresponding row for each genegse26953_f-v all shear diff expressed3fHAVECsvsvHAVECs exposed to same shear stress – Oscillatory2.6084DIFF Column details the FOLD CHANGE for the corresponding row for each genegse26953_oscillatory shear -f and v diff expressed4fHAVECsvsvHAVECs exposed to same shear stress – Laminar2.863DIFF Column details the FOLD CHANGE for the corresponding row for each genegse26953_laminar shear -f and v diff expressed5fHAVECs exposed to different shear stresses – Oscillatory vs Laminar 2.471052DIFF Column details the FOLD CHANGE for the corresponding row for each genegse26953_side f - oscillatory and laminar shear diff expressed6vHAVECs exposed to different shear stresses – Oscillatory vs Laminar2.675964DIFF Column details the FOLD CHANGE for the corresponding row for each genegse26953_side v -oscillatory and laminar shear diff expressed7Calcified vs Normal human AV3.27130DIFF Column details the FOLD CHANGE for the corresponding row for each genegse12644 Diff expressed _disease genesPrincipal Component Analysis: GSE12644 : Calcified vs normal human AV samples Heat Map: GSE26953 :Sheared HAVECs sample data. Heat Map: GSE12644 : Calcified vs normal human AV samplesEigenvalues and variance along each principal component axis (eigenvector)PCAEigenvalue% of VariancePCA 117.46687.3PCA 20.7383.7PCA 30.3241.62D Plots2514600381000003D plotBlue: Normal aortic valve, Red: Calcified aortic valveFigure 1 Figure 2Figure 1 : A 87.3% of the variance is shown along the first principal component axis. Two groupings are clearly demonstrated in the PCA, however the normal and diseased aortic valve (blue and red respectively) are not the dividing factors. The grouping element is unknown.Figure 2 : The PCA here demonstrates the third principle component axis with a variance of 1.6%.In both Figure 1 and Figure 2 the second principle component axis captures a variance of 3.7%. The PCA in both figures show that the normal aortic valves lie in the positive region and the calcified aortic valves represented by the red balls have negative readings along both axis ranging from 0 to -0.5. Figure 3Figure 3: This PCA shows no obvious grouping among the variables. GSE26953 : Sheared HAVECs sample dataEigenvalues and variance along each principal component axis (eigenvectors)PCAEigenvalue% of VariancePCA 17.10529.6PCA 26.21225.9PCA 32.0288.52D plot3D plotBlue: Fibrosa, Oscillatory shearGreen: Ventricularis, Laminar shearRed: Fibrosa, Laminar shearBrown: Ventricularis, Oscillatory shearFigure 1 Figure 2Figure 1: The variables which were exposed to laminar and oscillatory shear are represented in the PCA as two distinct groups. However there is no distinct pattern among the ventricularis and the fibrosa tissue. Along the first principal component there is a 29.6% variance.Figure 2: This PCA shows no grouping among the different aortic valves. Along the third principal component there is a 8.5% variance.Figure 3The aortic valves exposed to the laminar shear (red and green) and the valves exposed to the oscillatory shear (blue and brown) show up on either sides of the Y-axis, with the former being on negative side and the later in the positive region. Again in this PCA we cannot identify a grouping among the fibrosa and the ventricularis variables.Gene Ontology and Pathway Analysis: Steps: The Pathway analysis was performed using PATH VISIO 2- with WIKIPATHS (Analysis Collection Pathways) to identify any pathways containing up regulated/down regulated genes.For GSE12466- Up regulated genes are blue and down regulated genes are red. A gradient color scheme was applied. The up regulated genes were selected if the fold was > 1 and down regulated genes were selected if fold was < -1. All probes were subject to -log(p-vaIue) > 1.3 selection criteria.For GSE26593- down regulated genes were blue and up regulated genes were red. A gradient color scheme was applied. Down regulated genes were selected if fold value < 0 and up regulated genes were selected if fold value > 0. The fold values in these data sets were small. The selection for all records was -log(p-value) > 1.3. Not all samples provided pathways using these methods. In some cases no z value was calculated.Other PATH ANALYSIS tools were also attempted. Cytoscape, David, GenMapp CS Files and GSEA. GenMApp CS provided output similar to PATHVISIO but did not seem to provide an easy way to determine which paths could be used- in other words it displayed all paths- 181 of them. GSEA- This one utility needed the original affymetrix probe data for all samples but only containing the selected genes . We had used the JIMP data which did not contain this level of detail. The original JIMP tables containing the affymetrix and illumina data contain all original probes not just the selected probes. Most of these utilities need excel data saved as tab delimited files. JIMP files cannot be read into them and we cannot access jump from home. David did not seem to provide pathway 'pictures' and deciphering the output did not seem easy. We?also tried using GOEAST for Pathway Analysis, but could not get a decent diagram for GSE12466 (Calcified vs healthy Aortic) with more than 10 genes. We also couldn't get a diagram for the other study GSE26593 Osc vs Laminar data. GOEAST was abending or gave errors after waiting a long awhile.However, with whatever different analysis we performed, we nailed it down to the following important pathways and processes that regulated by the genes in response to different treatments or conditions, which are explained in detail below. Pathways: GSE12644 (Calcified vs Healthy Human AVs)Pathway regulatedWnt Signaling Pathway and PleuripotencyStatin PathwaySenescence and AutophagyMyometrial Relaction and ContractionFocal AdhesionFatty Acid Beta OxidationApoptosisGSE26953 -Fibrosa side: Oscillatory vs LaminarNucelotide metabolismSerotonin Receptor 2 & ELK-SRF/GATA4 signalingBlood Clotting CascadeFAS Pathway & Stress InductionTryptophan MetabolismAD Signaling PathwaySerotonin Receptor 4-6-7-and NR3C SignalingApoptosis ModulationCompliment and Coagulation CascadesOsteopontin SignalingHeart DevelopmentFatty Acid BiosythesisWnt SignalingGSE26953-Ocsillatory Shear on Fibrosa and Ventricularis sidesNo Pathways identifiedGSE26953- Ventricularis side: Oscillatory & Laminar ShearSerotonin Receptor 2 and ELK-SRF/GATA4 signalingBlood Clotting CascadeTryptophan metabolismSerotonin Receptor 4/6/7 and NR3C SignalingHeart DevelopmentmiRs in Muscle Cell DifferentiationNucleotide MetabolismID signaling pathwayComplement and Coagulation CascadesFatty Acid Beta OxidationOsteopontin SignalingFatty Acid BiosynthesisEndochondral OssificationIntegrated Pancreatic Cancer PathwayAndrogen receptor signaling pathwaySelenium PathwayWnt Signaling PathwayG Protein Signaling PathwaysGSE26953 - Laminar Shear - fibrosa and ventricularisNo Pathways foundGene Ontology: Calcified vs Normal Human AV samples: We first generated a list of processes and the associated number of genes that are altered or regulated in the calcified valves compared to normal valves. Following are the important biological functions and the corresponding number of genes associated with them that are significantly upregulated in calcified human AVs compared to normal human AVs. This data has been sorted based on two parameters: Important processes related to valve physiology and pathology as well as the p-value. This list will be used as a guide to test our hypothesis if the oscillatory shear on fibrosa side would trigger any of the genes that are associated with the calcified valves. OntologyTermNo. of Genesp-valuebiological_processcardiovascular system development222.18E-10biological_processresponse to wounding213.67E-10biological_processresponse to chemical stimulus301.71E-07biological_processresponse to stress331.87E-07biological_processcell migration151.98E-07biological_processwound healing121.55E-06biological_processcellular process883.35E-06biological_processnegative regulation of response to stimulus153.35E-06biological_processinflammatory response125.05E-06biological_processresponse to stimulus542.14E-05biological_processtissue morphogenesis128.27E-05biological_processosteoblast differentiation50.001503143biological_processangiogenesis80.002444354biological_processwound healing, spreading of epidermal cells30.003180017biological_processwound healing, spreading of cells30.003180017biological_processheart development90.00575483biological_processregulation of cell proliferation160.006280226biological_processresponse to external stimulus130.006280226biological_processnegative regulation of antigen processing and presentation20.006280226biological_processregulation of nitric oxide mediated signal transduction20.006280226biological_processossification60.015182975biological_processcell differentiation230.015424909cellular_componentextracellular matrix1839.93E-24molecular_functionextracellular matrix structural constituent174.07E-18molecular_functionplatelet-derived growth factor binding115.34E-17molecular_functionSMAD binding50.003407602Sheared HAVECs: We obtained the processes and the associated number of genes, which are regulated by different treatments: Laminar vs shear as well as side-dependent. But since we are looking at the treatment conditions that may potentially cause calcification, which is the effect of oscillatory shear on fibrosa side, we narrowed our ontology list based on the above table and listed the most relevant and important processes as follows. Overall shear response: Oscillatory vs LaminarOntologyTermNo. of genespbiological_processregulation of cellular process6158.45E-34biological_processdevelopmental process2627.73E-13biological_processtranslation789.77E-13biological_processcellular response to stimulus3123.09E-12biological_processmulticellular organismal development2347.57E-11biological_processanatomical structure development2093.09E-10biological_processsystem development1771.47E-08biological_processblood vessel development351.85E-08biological_processvasculature development353.83E-08biological_processsignaling2846.98E-08biological_processcell communication2917.20E-08biological_processangiogenesis251.13E-06biological_processregulation of signaling921.94E-06biological_processcell motility392.59E-06biological_processcellular lipid metabolic process575.50E-06biological_processregulation of cell proliferation711.06E-05biological_processintracellular protein transport511.11E-05biological_processcell migration351.20E-05biological_processnegative regulation of metabolic process691.26E-05biological_processregulation of signal transduction831.58E-05biological_processcardiovascular system development452.26E-05biological_processcell death669.42E-05biological_processcell differentiation1200.000145769biological_processnegative regulation of cell cycle380.000615823biological_processcellular homeostasis450.000650469biological_processnegative regulation of cell proliferation380.000678886biological_processregulation of cell migration190.003357046biological_processregulation of cell motility190.003357046biological_processcellular response to stress510.00797229biological_processnegative regulation of cell communication230.020000129biological_processcell-matrix adhesion160.026543478biological_processnitric oxide metabolic process50.030876446biological_processnegative regulation of signal transduction220.031319124biological_processnegative regulation of transcription, DNA-dependent300.032141373biological_processregulation of MAP kinase activity180.034176127biological_processcell cycle660.036313315biological_processtissue homeostasis70.040350696biological_processnegative regulation of signaling220.04130435biological_processnegative regulation of hormone metabolic process30.04189894biological_processnegative regulation of smooth muscle cell migration30.04189894biological_processtissue development520.045163795biological_processregulation of cell growth260.047520856biological_processnegative regulation of blood coagulation50.048777412biological_processnegative regulation of hemostasis50.048777412biological_processcell proliferation370.049297913biological_processRas protein signal transduction170.057022382biological_processnegative regulation of response to stimulus240.062378208biological_processwound healing170.081455496biological_processcell development430.081615089biological_processchemical homeostasis370.081727329biological_processregulation of programmed cell death450.088334937biological_processregulation of cell death450.090526108biological_processregulation of actin polymerization or depolymerization100.09069631biological_procession transmembrane transport80.091831322biological_processregulation of I-kappaB kinase/NF-kappaB cascade160.091831322biological_processresponse to oxidative stress160.091831322cellular_componentcell13572.98E-166cellular_componentcell part13572.98E-166cellular_componentintracellular12304.80E-165cellular_componentintracellular part11991.07E-161cellular_componentendomembrane system1415.04E-12molecular_functionphosphotransferase activity, alcohol group as acceptor931.57E-08molecular_functionantioxidant activity100.065424983molecular_functionnucleoside-triphosphatase regulator activity380.091831322Fibrosa side: Oscillatory vs Laminar shear: OntologyTermNo. of genesp - valuebiological_processcellular process5713.49E-57biological_processregulation of cellular process3408.01E-19biological_processresponse to stimulus2414.25E-12biological_processcellular component organization1154.84E-09biological_processmulticellular organismal development1417.93E-09biological_processresponse to stress932.79E-08biological_processcellular response to stimulus1793.52E-08biological_processgene expression832.26E-07biological_processanatomical structure development1223.73E-07biological_processtranslation444.50E-07biological_processsignal transduction1553.57E-06biological_processcell communication1671.67E-05biological_processcell motility257.28E-05biological_processcell migration230.000120665biological_processregulation of signal transduction510.000195557biological_processregulation of cell cycle360.000222076biological_processnegative regulation of gene expression260.000329267biological_processregulation of gene expression1250.000425113biological_processregulation of response to stimulus580.000498521biological_processregulation of cell communication340.001408852biological_processresponse to wounding310.001408852biological_processregulation of cell migration140.002100465biological_processregulation of cell motility140.002100465biological_processlipopolysaccharide-mediated signaling pathway40.00522278biological_processnegative regulation of blood coagulation50.005312838biological_processangiogenesis130.006336822biological_processnucleocytoplasmic transport140.006676118biological_processnuclear transport140.007394041biological_processcardiovascular system development250.007571576biological_processregulation of cell proliferation380.011687283biological_processlipid transport140.012033119biological_processpositive regulation of macromolecule metabolic process380.012434336biological_processregulation of coagulation60.012434336biological_processcell differentiation670.012981489biological_processcellular homeostasis260.019414487biological_processlipid localization140.021018667biological_processregulation of response to external stimulus100.034446655biological_processpositive regulation of response to external stimulus60.034446655biological_processpositive regulation of MAP kinase activity100.034446655biological_processregulation of wound healing50.041267336biological_processanatomical structure morphogenesis460.04722417biological_processgene silencing60.049849136biological_processcellular response to stress300.057586055biological_processpositive regulation of endothelial cell migration30.05883972biological_processregulation of MAP kinase activity120.059244202biological_processcell death340.064616034biological_processapoptotic process310.065829318cellular_componentcell7441.85E-90cellular_componentcell part7441.85E-90cellular_componentintracellular6691.69E-86cellular_componentintracellular part6475.68E-82cellular_componentnucleosome90.006395077cellular_componentmembrane-bounded vesicle320.007490244cellular_componentextracellular region880.009427704cellular_componentcell junction310.026179387molecular_functiontransition metal ion binding1340.000126894molecular_functionoxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen130.006676118molecular_functionL-ascorbic acid binding60.006767938molecular_functioncalcium ion binding550.007160141Fibrosa vs Ventricularis side: Oscillatory shearOntologyTermgenespbiological_processregulation of catabolic process20.032616666biological_processcytoplasmic sequestering of NF-kappaB10.08034134biological_processfatty acid alpha-oxidation10.080861475biological_processregulation of Cdc42 protein signal transduction10.080861475biological_processregulation of Cdc42 GTPase activity10.080861475biological_processnegative regulation of transmembrane transport10.085464824biological_processnegative regulation of protein import into nucleus10.085464824biological_processnegative regulation of NF-kappaB import into nucleus10.085464824biological_processnegative regulation of transcription factor import into nucleus10.085464824biological_processcytoplasmic sequestering of transcription factor10.085464824biological_processnegative regulation of I-kappaB kinase/NF-kappaB cascade10.085464824biological_processnegative regulation of nucleocytoplasmic transport10.085464824biological_processnegative regulation of intracellular protein transport10.085464824biological_processregulation of Rho GTPase activity10.085464824biological_processpositive regulation of Ras GTPase activity10.085464824biological_processpositive regulation of Rho GTPase activity10.085464824biological_processpositive regulation of GTPase activity10.085464824biological_processpositive regulation of protein complex assembly10.086473584biological_processnegative regulation of intracellular transport10.087431714biological_processregulation of NF-kappaB import into nucleus10.092939231molecular_functionRac GTPase activator activity10.08034134molecular_functionNF-kappaB binding10.085464824molecular_functionRac GTPase binding10.085464824molecular_functionRho GTPase activator activity10.094580619Discussion: We were able to generate pathway as well as the gene ontology details for all our comparison groups. PCA analysis indicated that calcified vs healthy human AVs sample data are distinctly grouped into two. Further pathway analysis showed that these calcified samples expressed genes that involved in the Apoptosis, Wnt signaling, oxidation and statin pathways. These pathways when altered have been known to be involved in the AV disease progression ADDIN EN.CITE <EndNote><Cite><Author>Miller</Author><Year>2011</Year><RecNum>153</RecNum><DisplayText>[6]</DisplayText><record><rec-number>153</rec-number><foreign-keys><key app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">153</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Miller, Jordan D.</author><author>Weiss, Robert M.</author><author>Heistad, Donald D.</author></authors></contributors><titles><title>Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms</title><secondary-title>Circulation Research</secondary-title></titles><periodical><full-title>Circulation Research</full-title></periodical><pages>1392-1412</pages><volume>108</volume><number>11</number><dates><year>2011</year><pub-dates><date>May 27, 2011</date></pub-dates></dates><urls><related-urls><url>;[6]. Further gene ontology revealed that, the calcified valves expressed genes that negatively alter basic cell functions such as cell death, proliferation, migration and development apart from the process that are associated with disease initiating pathways such as angiogenesis, inflammation (via NF-KB pathway), apoptosis, ossification and osteogenesis. These results are also in good agreement with the published resultsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3NzZTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [13]. In order to test our hypothesis, which is fibrosa side when exposed to oscillatory shear stress, expresses genes involved in AV disease progression, we primarily focused on the following groupsOverall shear effects: oscillatory vs laminar shear stress Fibrosa: oscillatory vs laminar shear stressOscillatory shear stress: Fibrosa vs VentricularisWe observed that when fibrosa was exposed to oscillatory vs laminar shear stress, some of the pathways associated with disease were identified, such as osteopontin, wnt signaling, serotonin receptor pathway, blood coagulation inducer, which were not observed on ventricularis side. Further, specifically, the processes related to anatomic development were seen preferentially on fibrosa when exposed to oscillatory shear. This can be justified stating that, although fibrosa and ventricularis sides are part of the same valve, their composition differs, partly due to the conditioning of the different mechanical stimuli and partly due to genetics. Perhaps, this can also explain the preferential inflammation and calcification of the fibrosa side, under altered mechanical stimuli, compared to ventricularis side, as also reported in an ex vivo study ADDIN EN.CITE <EndNote><Cite><Author>Sucosky</Author><Year>2009</Year><RecNum>71</RecNum><DisplayText>[7]</DisplayText><record><rec-number>71</rec-number><foreign-keys><key app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">71</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sucosky, Philippe</author><author>Balachandran, Kartik</author><author>Elhammali, Adnan</author><author>Jo, Hanjoong</author><author>Yoganathan, Ajit P.</author></authors></contributors><titles><title>Altered Shear Stress Stimulates Upregulation of Endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-{beta}1-Dependent Pathway</title><secondary-title>Arterioscler Thromb Vasc Biol</secondary-title></titles><periodical><full-title>Arterioscler Thromb Vasc Biol</full-title></periodical><pages>254-260</pages><volume>29</volume><number>2</number><dates><year>2009</year><pub-dates><date>February 1, 2009</date></pub-dates></dates><urls><related-urls><url>;[7]. Genes involved in other functions such as cell cycle, migration, development, proliferation were expressed in all different groups, but at different levels (or numbers). However, the published results indicated other novel mechanosensitive pathways that were not detected by our analysis. This could be due to the differences in the analysis softwares ( such as using JIMP vs SAM, open source tools for pathways and ontology vs using Ingenuity Pathway Analysis etc) ADDIN EN.CITE <EndNote><Cite><Author>Holliday</Author><Year>2011</Year><RecNum>129</RecNum><DisplayText>[12]</DisplayText><record><rec-number>129</rec-number><foreign-keys><key app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Holliday, Casey J.</author><author>Ankeny, Randall F.</author><author>Jo, Hanjoong</author><author>Nerem, Robert M.</author></authors></contributors><titles><title>Discovery of Shear- and Side-specific mRNAs and miRNAs in Human Aortic Valvular Endothelial Cells</title><secondary-title>American Journal of Physiology - Heart and Circulatory Physiology</secondary-title></titles><dates><year>2011</year><pub-dates><date>June 24, 2011</date></pub-dates></dates><urls><related-urls><url>;[12]. Albeit the differences in the pathways identified, we found some of the common pathways between fibrosa exposed to oscillatory shear and calcified human valves. This thus indicated that fibrosa when exposed to low magnitude disturbed shear stresses such as low oscillatory shear can express genes that are involved in AV disease progression. The negative effects of low magnitude oscillatory shear has been observed even in the atherosclerosis of blood vessels, suggesting that AV disease progression can potentially share some similarities with that of atherosclerosis ADDIN EN.CITE <EndNote><Cite><Author>Agmon</Author><Year>2001</Year><RecNum>2</RecNum><DisplayText>[14]</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="0vxfdre2555vaie59sgvwwt52s5eaf9d9stz">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Agmon, Yoram</author><author>Khandheria, Bijoy K.</author><author>Meissner, Irene</author><author>Sicks, JoRean D.</author><author>O'Fallon, W. Michael</author><author>Wiebers, David O.</author><author>Whisnant, Jack P.</author><author>Seward, James B.</author><author>Tajik, A. Jamil</author></authors></contributors><titles><title>Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease?: Insights from a population-based study</title><secondary-title>J Am Coll Cardiol</secondary-title></titles><pages>827-834</pages><volume>38</volume><number>3</number><dates><year>2001</year><pub-dates><date>September 1, 2001</date></pub-dates></dates><urls><related-urls><url>;[14]. References: ADDIN EN.REFLIST 1.Rajamannan, N.M., R.O. Bonow, and S.H. Rahimtoola, Calcific aortic stenosis: an update. Nat Clin Pract Cardiovasc Med, 2007. 4(5): p. 254-262.2.Otto, C.M., et al., Association of Aortic-Valve Sclerosis with Cardiovascular Mortality and Morbidity in the Elderly. N Engl J Med, 1999. 341(3): p. 142-147.3.Stewart, M.D.F.B.F., et al., Clinical Factors Associated With Calcific Aortic Valve Disease. Journal of the American College of Cardiology, 1997. 29(3): p. 630-634.4.Rabkin, S.W., The association of hypertension and aortic valve sclerosis. Blood Pressure, 2005. 14(5): p. 264-272.5.Thubrikar, M., The aortic valve1990, Boca Raton, Fla. :: CRC Press.6.Miller, J.D., R.M. Weiss, and D.D. Heistad, Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms. Circulation Research, 2011. 108(11): p. 1392-1412.7.Sucosky, P., et al., Altered Shear Stress Stimulates Upregulation of Endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-{beta}1-Dependent Pathway. Arterioscler Thromb Vasc Biol, 2009. 29(2): p. 254-260.8.Weston, M. and A. Yoganathan, Biosynthetic Activity in Heart Valve Leaflets in Response to In Vitro Flow Environments. Annals of Biomedical Engineering, 2001. 29(9): p. 752-763.9.Sorescu, G.P., et al., Bone Morphogenic Protein 4 Produced in Endothelial Cells by Oscillatory Shear Stress Induces Monocyte Adhesion by Stimulating Reactive Oxygen Species Production From a Nox1-Based NADPH Oxidase. Circulation Research, 2004. 95(8): p. 773-779.10.Ge, L. and F. Sotiropoulos, Direction and Magnitude of Blood Flow Shear Stresses on the Leaflets of Aortic Valves: Is There a Link With Valve Calcification? Journal of Biomechanical Engineering, 2010. 132(1): p. 014505.11.Hsu, S.Y., et al., Aortic valve sclerosis is an echocardiographic indicator of significant coronary disease in patients undergoing diagnostic coronary angiography. International Journal of Clinical Practice, 2005. 59(1): p. 72-77.12.Holliday, C.J., et al., Discovery of Shear- and Side-specific mRNAs and miRNAs in Human Aortic Valvular Endothelial Cells. American Journal of Physiology - Heart and Circulatory Physiology, 2011.13.Bosse, Y., et al., Refining Molecular Pathways Leading to Calcific Aortic Valve Stenosis by Studying Gene Expression Profile of Normal and Calcified Stenotic Human Aortic Valves. Circulation-Cardiovascular Genetics, 2009. 2(5): p. 489-U185.14.Agmon, Y., et al., Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease?: Insights from a population-based study. J Am Coll Cardiol, 2001. 38(3): p. 827-834. ................
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