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Identification of key pathways and genes in carotid atherosclerosis through bioinformatics analysis of RNA-seq data.

ABSTRACT: While acknowledging carotid atherosclerosis (CAS) as a risk factor for ischemic stroke, reports on its pathogenesis are scarce. This study aimed to explore the potential mechanism of CAS through RNA-seq data analysis. Carotid intima tissue samples from CAS patients and healthy subjects were subjected to RNA-seq analysis, which yielded, 1,427 differentially expressed genes (DEGs) related to CAS. Further, enrichment analysis (Gene Ontology, KEGG pathway, and MOCDE analysis) was performed on the DEGs. Hub genes identified via the protein-protein interaction network (PPI) were then analyzed using TRRUST, DisGeNET, PaGenBase, and CMAP databases. Results implicated inflammation and immunity in the pathogenesis of CAS. Also, lung disease was associated with CAS. Hub genes were expressed in multiple diseases, mainly regulated by RELA and NFKB1. Moreover, three small-molecule compounds were found via the CMAP database for management of CAS; hub genes served as potential targets. Collectively, inflammation and immunity are the potential pathological mechanisms of CAS. This study implicates CeForanide, Chenodeoxycholic acid, and 0317956-0000 as potential drug candidates for CAS treatment.

SUBMITTER: Li Z

PROVIDER: S-EPMC8148499 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Identification of key pathways and genes in carotid atherosclerosis through bioinformatics analysis of RNA-seq data.

Li Zhongchen Z Hao Jiheng J Chen Kun K Jiang Qunlong Q Wang Peijian P Xing Xiaohui X Wang Jiyue J Zhang Yinjiang Y Xiao Yilei Y Zhang Liyong L

Aging 20210511 9

While acknowledging carotid atherosclerosis (CAS) as a risk factor for ischemic stroke, reports on its pathogenesis are scarce. This study aimed to explore the potential mechanism of CAS through RNA-seq data analysis. Carotid intima tissue samples from CAS patients and healthy subjects were subjected to RNA-seq analysis, which yielded, 1,427 differentially expressed genes (DEGs) related to CAS. Further, enrichment analysis (Gene Ontology, KEGG pathway, and MOCDE analysis) was performed on the DE ...[more]

PMID: 33973530

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Project description:Renal fibrosis (RF) is the common pathological manifestation and central treatment target of multiple chronic kidney diseases with high morbidity and mortality. Currently, the molecular mechanisms underlying RF remain poorly understood, and exploration of RF-related hub targets and pathways is urgently needed. In this study, two classical RF rat models (adenine and UUO) were established and evaluated by HE, Masson and immunohistochemical staining. To clear molecular mechanisms of RF, differentially expressed genes (DEGs) were identified using RNA-Seq analysis, hub targets and pathways were screened by bioinformatics (functional enrichment analyses, PPI network, and co-expression analysis), the screening results were verified by qRT-PCR, and potential drugs of RF were predicted by network pharmacology and molecular docking. The results illustrated that renal structures were severely damaged and fibrotic in adenine- and UUO-induced models, as evidenced by collagen deposition, enhanced expressions of biomarkers (TGF-β1 and α-SMA), reduction of E-cadherin biomarker, and severe renal function changes (significantly decreased UTP, CREA, Ccr, and ALB levels and increased UUN and BUN levels), etc. 1189 and 1253 RF-related DEGs were screened in the adenine and UUO models, respectively. Two key pathways (AGE-RAGE and NOD-like receptor) and their hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) were identified by PPI networks, co-expressed relationships, and qRT-PCR verification. Furthermore, various reported herbal ingredients (curcumin, resveratrol, honokiol, etc.) were considered as important drug candidates due to the strong binding affinity with these hub targets. Overall, this study mainly identified two key RF-related pathways (AGE-RAGE and NOD-like receptor), screened hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) that involved inflammation, ECM formation, myofibroblasts generation, and pyroptosis, etc., and provided referable drug candidates (curcumin, resveratrol, honokiol, etc.) in basic research and clinical treatment of RF.

Project description:BackgroundAtherosclerosis is a major contributor to cardiovascular events, however, its molecular mechanism remains poorly known. Animal models of atherosclerosis can be a valuable tool to provide insights into the etiology, pathophysiology, and complications of atherosclerosis. In particular, Tibetan minipigs are a feasible model for studying diet-related metabolic and atherosclerotic diseases.MethodsWe used vascular transcriptomics to identify differentially expressed genes (DEGs) in high fat/cholesterol (HFC) diet-fed Tibetan minipig atherosclerosis models, analyzed the DEGs gene ontology (GO) terms, pathways and protein-protein interactions (PPI) networks, and identified hub genes and key modules using molecular complex detection (MCODE), Centiscape and CytoHubba plugin. The identified genes were validated using the human carotid atherosclerosis database (GSEA 43292) and RT-PCR methods.ResultsOur results showed that minipigs displayed obvious dyslipidemia, oxidative stress, inflammatory response, atherosclerotic plaques, as well as increased low-density lipoprotein (LDL) and leukocyte recruitment after 24 weeks of HFC diet feeding compared to those under a regular diet. Our RNA-seq results revealed 1716 DEGs in the atherosclerotic/NC group, of which 1468 genes were up-regulated and 248 genes were down-regulated. Functional enrichment analysis of DEGs showed that the HFC diet-induced changes are related to vascular immune-inflammatory responses, lipid metabolism and muscle contraction, indicating that hypercholesterolemia caused by HFC diet can activate innate and adaptive immune responses to drive atherosclerosis development. Furthermore, we identified four modules from the major PPI network, which are implicated in cell chemotaxis, myeloid leukocyte activation, cytokine production, and lymphocyte activation. Fifteen hub genes were discovered, including TNF, PTPRC, ITGB2, ITGAM, VCAM1, CXCR4, TYROBP, TLR4, LCP2, C5AR1, CD86, MMP9, PTPN6, C3, and CXCL10, as well as two transcription factors (TF), i.e. NF-ĸB1 and SPI1. These results are consistent with the expression patterns in human carotid plaque and were validated by RT-PCR.ConclusionsThe identified DEGs and their enriched pathways provide references for the development and progression mechanism of Tibetan minipig atherosclerosis model induced by the HFC diet.

Dataset Information

Identification of key pathways and genes in carotid atherosclerosis through bioinformatics analysis of RNA-seq data.

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Identification of key pathways and genes in carotid atherosclerosis through bioinformatics analysis of RNA-seq data.

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