Atherosclerosis induced by familial hypercholesterolemia (FHC) Essay

Abstraction

Aim: The survey was aimed to research the possible mechanism underlying coronary artery disease development induced by familial hypercholesteremia ( FHC ) and place the possible mark cistrons for coronary artery disease intervention by bioinformatics analysis.

Methods:The microarray informations of GSE13985 was downloaded from Gene Expression Omnibus ( GEO ) database which were developed by 5 blood samples from FHC samples and 5 1s from controls. The differentially expressed cistrons ( DEGs ) between FHC and normal samples were analyzed. The protein-protein interaction ( PPI ) web was constructed and Kyoto Encyclopedia of Genes and Genomes ( KEGG ) enrichment analysis was performed. Additionally, faculty analysis and Gene ontology ( GO ) analysis for faculty cistrons were performed.

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Consequences:Entire 394 DEGs were obtained, including 125 up- and 269 down-regulated cistrons. Ribosomal proteins, such as ribosomal protein L9 ( RPL9 ) , ribosomal protein L35 ( RPL35 ) and ribosomal protein S7 ( RPS7 ) , were hub nodes in PPI web. KEGG pathways consequences showed that the DEGs were significantly enriched in ribosome and oxidative phosphorylation tracts. Ribosome proteins related cistrons were identified in ribosome tract. Cytochrome hundred oxidase cistrons, including cytochrome hundred oxidase ( COX ) fractional monetary unit VIIa polypeptide 2 (COX7A2) , COX fractional monetary unit VIIb (COX7B) , COX fractional monetary unit VIIc (COX7C) and COX fractional monetary unit VIc (COX6C) , were enriched in oxidative phosphorylation tract. Additionally, faculty analysis and GO enrichment analysis consequences showed that ribosome proteins were the of import proteins in FHC.

Decision:The ribosome and oxidative phosphorylation tracts may be closely associated with coronary artery disease development induced by FHC. Ribosome proteins related cistrons and cytochrome degree Celsius oxidase cistrons may be possible curative mark cistrons for coronary artery disease.

Keywords: coronary artery disease ; familial hypercholesteremia ; differentially expressed cistrons ; bioinformatics analysis

Introduction

Atherosclerosis is a chronic disease, which is caused by the deposition of lipid ( chiefly cholesterin and cholesterin esters ) in the intima of the arterial wall, taking to the arterial wall thickness ( Moghadasian 2002 ) . It is proved that one of the taking hazard factors for development of coronary artery disease is familial hypercholesteremia ( FHC ) ( Cheung & A ; Lam 2010 ) . FHC is an autosomal dominant upset, which is characterized with high cholesterin degrees, specially a high degree of low-density lipoprotein ( LDL ) ( Aliev et al. 2003 ) . FHC coronary artery disease is one of the prima causes for decease among the population worldwide. Therefore, an improved apprehension mechanism on the pathogenesis of coronary artery disease induced by FH C would provide new penetrations for the diagnosing and intervention of coronary artery disease.

Many surveies in molecular biological science have been done to decode the pathogenesis of coronary artery disease caused by FHC High LDL-cholesterol is a hazard factor for coronary artery disease and omission in the cistron for the LDL receptor (LDLR) is associated with FHC ( Hobbs et al. 1987 ) . Smildeet Al. reported that aggressive LDL-cholesterol decrease was accompanied by cut downing the coronary artery disease patterned advance in FHC patients ( Smilde et al. 2001 ) . Based on the old research at cistron degree, the over-expression of cholesteryl ester transportation protein (CETP) was found to be able to cut down the degree of cholesterin ( Ishibashi et al. 1993 ) . In add-on, lessening in interleukin-12 production associating the 12/15-lipoxygenase tract was associated with decreased coronary artery disease in a mouse theoretical account of FHC ( Zhao et al. 2002 ) . However, the molecular mechanism of coronary artery disease is non to the full understood and the cistron therapy for coronary artery disease is deficient.

In this survey, we applied the bioinformatics methods to download the microarray informations ( GSE13985 ) and analyze the differentially expressed cistrons ( DEGs ) of white blood cells between FHC and normal samples. Protein-protein interaction ( PPI ) web was constructed for DEGs and Kyoto Encyclopedia of Genes and Genomes ( KEGG ) enrichment analysis was performed. Besides, faculty analysis and Gene ontology ( GO ) analysis for faculty cistrons were performed to gauge the important cistrons and their corresponding maps. The intent of this work was to research the possible mechanism underlying coronary artery disease development induced by FHC and uncover the mark cistron for coronary artery disease intervention.

Methods

Affymetrixmicroarrayvitamin Data

The RNA microarray informations [ A1 ] of GSE13985 was obtained from the Gene Expression Omnibus ( GEO ) database in National Center for Biotechnology Information ( NCBI, hypertext transfer protocol: //www.ncbi.nlm.nih.gov/geo/ ) , which was deposited by ReA?en et Al. on December 18, 2008.. Entire 10 white blood samples were used for look forms development, including 5 samples from patients with FHC and 5 normal samples. The natural information and investigation note information were downloaded based on the platform of GPL570 ( Affymetrix Human Genome U133 Plus 2.0 Array ) ( Affymetrix Inc. , Santa Clara, California, USA ) .

DatasPreprocessing andvitamin Differentiallyvitamin Expressedgeast northeastanalysis

The probe-level informations in.CEL file s were converted into look steps. The informations were foremost preprocessed utilizing the Affy bundle ( hypertext transfer protocol: //www.bioconductor.org/packages/release/bioc/html/affy.html ) ( Team 2012 ) in R linguistic communication. The probe-level informations were converted into the cistron look steps. If multiple investigations corresponded to a same cistron, the average look value was calculated to stand for the cistron look degree. The losing values were imputed utilizing the K-nearest Neighbors ( KNN ) method ( Troyanskaya et al. 2001 ) . Then the informations were quantile normalized with the Affy bundle ( Team 2012 ) in R.

The differentially expressed cistrons ( DEGs ) between FHC and normal samples were analyzed with the application of limma bundle ( hypertext transfer protocol: //master.bioconductor.org/packages/release/bioc/html/limma.html ) ( Smyth 2004 ) in R.Phosphorus-value & lt ; 0.05 and | fold alteration ( FC ) | & gt ; 1.5 [ A2 ] ( | log2FC | & gt ; 0.585 ) were defined as the threshold value.

Protein-protein interaction web

Search Tool for the Retrieval of Interacting Genes ( STRING, hypertext transfer protocol: //www.string-db.org/ ) ( Szklarczyk et al. 2011 ) is a public database for foretelling cistron interactions with a assurance mark. The up-regulated cistron and down-regulated 1s were analyzed to build the protein-protein interaction ( PPI ) web utilizing STRING. Connectivity degree represents the figure of borders linked to a given node. The of import nodes with high grade in the web were obtained, viz. hub nodes. The interactions with assurance mark & gt ; 0.9 were collected as campaigners for farther analysis. The PPI web was visualized by Cytoscape package ( hypertext transfer protocol: //cytoscape.org/plugins.html ) ( Smoot et al. 2011 ) .

KEGG tracts analysis

KEGG cognition database ( hypertext transfer protocol: //www.kegg.jp/ ) ( Altermann & A ; Klaenhammer 2005 ) is a major database for pathways analysis, which identified the significantly enriched metabolic or signal tracts for mark cistrons. The Database for Annotation, Visualization and integrated find ( DAVID, hypertext transfer protocol: //david.abcc.ncifcrf.gov/ ) ( Huang da et Al. 2009 ) is an on-line tool that provides a comprehensive set of functional note for big list of cistrons. The KEGG tract enrichment analysis was carried out for DEGs in PPI web utilizing DAVID.Phosphorus-value & lt ; 0.05 was the cutoff standard for the functional enrichment analysis.

Meterodule analysis

Gene merchandises with the similar map can be clustered in the same faculty to modulate biological procedure ( BP ) . Molecular Complex Detection ( MCODE ) ( Bader & A ; Hogue 2003 ) is a method to observe dumbly connected parts in PPI webs. The faculty analysis of the PPI web was performed by the MCODE. The faculty with degree cutoff ? 2 ( each node in faculty with at least 2 grade ) and K-core ? 2 ( each node with at least 2 neighboring nodes ) were screened.

In order to research the maps of faculties, the DEGs of the faculty were subjected to Gene ontology ( GO ) analysis by the Bingo plugin of Cytoscape ( Maere et al. 2005 ) . In this survey, GO categories with fold find rate ( FDR ) & lt ; 0.05 were considered as important.

Consequences

Designation of DEGs

As shown in Figure 1, the natural look informations were normalized after preprocessed. A sum of 394 DEGs were obtained, including 125 up-regulated cistrons and 269 down-regulated cistrons.

PPI web analysis

As shown in Figure 2, the PPI web was constructed with 94 nodes and 220 borders. In these nodes, there were 25 up- and 69 down-regulated cistrons. [ A3 ] In this web, ribosomal protein L9 ( RPL9, degree = 22 ) , ribosomal protein L35 ( RPL35, degree = 20 ) , ribosomal protein S7 ( RPS7, degree = 19 ) and ribosomal protein L23 ( RPL23, degree = 18 ) were selected as hub nodes with the high connectivity grade. All of them were down-regulated cistrons.

KEGG tracts analysis

Entire 2 tracts were obtained in KEGG tracts analysis ( Table 1 ) . The DEGs were significantly enriched in ribosome (P-value = 4.89E-21 ) and oxidative phosphorylation (P-value = 2.96E-05 ) tracts. 21 DEGs, such asRPL9,RPL35,RPS7andRPL23, were identified in ribosome tract and all of them were ribosome proteins related cistrons. Besides, cytochrome degree Celsius oxidase cistrons such as cytochrome degree Celsius oxidase fractional monetary unit VIIa polypeptide 2 ( COX7A2 ) , cytochrome degree Celsius oxidase fractional monetary unit VIIb ( COX7B ) , cytochrome degree Celsius oxidase fractional monetary unit VIIc ( COX7C ) and cytochrome degree Celsius oxidase fractional monetary unit VIc ( COX6C ) were identified in oxidative phosphorylation tract.

Faculty analysis

Merely one faculty was selected in PPI web ( Figure 3 ) . The faculty web was constructed with 15 nodes. All of DEGs in this faculty were ribosome proteins with high connectivity grade.

The consequences of GO functional note for the DEGs in this faculty were shown in Table 2. The most significantly enriched GO BP term was translational elongation (P-value = 8.03E-34 ) . Other important GO BP footings included interlingual rendition, cellular supermolecule biosynthetic procedure and supermolecule biosynthetic procedure and so on.

Discussion

Atherosclerosis is a major cause of decease worldwide and FHC is an of import hazard factor for coronary artery disease ( Cheung & A ; Lam 2010 ) . Understanding the molecular mechanism of coronary artery disease induced by FHC is of critical importance for direction policy. In this survey, the research was based on the bioinformatics analysis of the cistron look profile informations of GSE13985 downloaded from GEO database to place DEGs between FHC and normal samples. Wholly, 394 DEGs including 125 up- and 269 down-regulated cistrons were selected. PPI web analysis showed that the ribosomal proteins, such as RPL9, RPL35 and RPS7, were hub nodes. KEGG pathways consequences showed that the DEGs were significantly enriched in ribosome and oxidative phosphorylation tracts. Ribosome proteins related cistrons and cytochrome degree Celsius oxidase cistrons (COX7A2,COX7B,COX7CandCOX6C) were identified in these tracts. Additionally, faculty analysis were besides showed that ribosome proteins were the of import proteins in FHC. These DEGs and their related maps may be involved in coronary artery disease development induced by FHC.

Ribosome is a big and complex cell organ, which was found within all life cells. In this survey, the ribosome tract was the important map. Ribosome proteins related cistrons, such as RPL9,RPL35andRPS7, were identified in this tract. It has been reported that ribosome proteins are associated with of import biological advancements, such as protein synthesis ( Ruvinsky & A ; Meyuhas 2006 ) , cell proliferation ( VolareviA‡ et al. 2000 ) and cell programmed cell death ( Khanna et al. 2003 ) . Dzau et Al. reported that vascular cell proliferation contributed to the pathobiology of coronary artery disease ( Dzau et al. 2002 ) .RPL17( belongs to ribosome proteins household ) acted as a vascular smooth musculus cell ( VAMC ) growing inhibitor and represented a possible curative mark to restrict carotid intima-media thickener ( Smolock et al. 2012 ) . Restricting carotid intima-media thickener can cut down the hazard to coronary artery disease ( Lorenz et al. 2006 ) . What’s more, ribosomal protein S6 kinase ( RPS6K ) is the cardinal mammalian mark of rapamycin ( mTOR ) effecter and mTOR tract is a cardinal regulator of cell growing via the ordinance of protein synthesis ( Jastrzebski et al. 2007 ) . Muelleret Al. reported that mTOR inhibitor strongly inhibited coronary artery disease development in LDLR-/-mice ( Mueller et al. 2008 ) . In this survey, ribosome proteins related cistrons were down-expressed in FHC samples and they were hub nodes in PPI web, proposing that these cistrons may play of import functions in coronary artery disease development induced by FHC through modulating ribosome tract.

Apart from ribosome proteins related cistrons and their map, oxidative phosphorylation tract was another of import map. Oxidative phosphorylation is the metabolic tract to let go of energy to reform adenosine triphosphate ( ATP ) in chondriosome cells ( Hatefi 1985 ) . The accretion of reactive O species ensuing from the instability of the development and riddance of the O free groups or inordinate consumption of exogenic oxidative substance can take to the cytotoxicity ( Delbosc et al. 2005 ) . It has been demonstrated that oxidative emphasis played a causal function in vascular diseases including hypercholesteremia and coronary artery disease ( Magenta et al. 2013 ) . In this survey, cytochrome hundred oxidase cistrons ( COX7A2, COX7B,COX7CandCOX6C) were identified in this map. It has been reported that cytochrome hundred oxidase regulates the oxidative phosphorylation in eucaryotic enzyme ( Ludwig et al. 2001 ) . Duttaet Al. reported thatCOX7Bas a mitochondrial negatron conveyance concatenation cistron was down-expressed in multiple induration patients, which reduced ATP production and caused chondriosomes disfunction ( Dutta et al. 2006 ) . The disfunction of chondriosome contributes to cardiovascular diseases by bring oning programmed cell death and alterations in mitochondrial morphology ( Williamson et al. 2010 ) . Therefore, we speculated that cytochrome degree Celsius oxidases played a cardinal function in mitochondrial map. In this survey, cytochrome hundred oxidase cistrons were down-expressed in FHC samples, proposing that deviant look of these cistrons may lend to the development of coronary artery disease by ordinance oxidative phosphorylation tract.

In drumhead,our survey shows thatThursdayvitamin Eribosome and oxidative phosphorylation tractsmay be closely associated withcoronary artery disease development induced by FHC.Ribosome proteins related cistrons and cytochrome degree Celsius oxidasecistronsmay bepossiblecurative mark cistronsforcoronary artery disease. However, farther experiments are still required to corroborate our findings.

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