Differentially expressed genes, lncRNAs, and competing endogenous RNAs in Kawasaki disease

Background Kawasaki disease (KD) is an acute and febrile systemic vasculitis of unknown etiology. This study aimed to identify the competing endogenous RNA (ceRNA) networks of lncRNAs, miRNAs, and genes in KD and explore the molecular mechanisms underlying KD. Methods GSE68004 and GSE73464 datasets were downloaded from the Gene Expression Omnibus. Differentially expressed lncRNAs (DElncRNAs) and genes (DEGs) in KD were identified using the criteria of p < 0.05 and | log2 (fold change) | ≥ 1. MicroRNAs (miRNAs) related to KD were searched from databases. The lncRNA-miRNA-mRNA networks involving the DElncRNAs and DEGs were constructed. Results A total of 769 common upregulated, 406 common downregulated DEGs, and six DElncRNAs were identified in the KD samples. The lncRNA-miRNA-mRNA network consisted of four miRNAs, three lncRNAs (including the upregulated PSORS1C3, LINC00999, and the downregulated SNHG5) and four DEGs (including the downregulated GATA3 and the upregulated SOD2, MAPK14, and PPARG). Validation in the GSE18606 dataset showed that intravenous immunoglobulin treatment significantly alleviated the deregulated profiles of the above RNAs in KD patients. Three ceRNA networks of LINC00999-hsa-miR-6780-SOD2, PSORS1C3-hsa-miR-216a-PPARG/MAPK14, and SNHG5-hsa-miR-132/hsa-miR-92-GATA3 were identified. Four genes were associated with functional categories, such as inflammatory response and vascular endothelial cell. Conclusions The ceRNA networks involve genes, such as SOD2, MAPK14, and PPARG, and lncRNAs, including PSORS1C3, LINC00999, and SNHG5, which might play a key role in the pathogenesis and development of KD by regulating inflammation.

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Functional benefits of corticosteroid and IVIG combination therapy in a coronary artery endothelial cell model of Kawasaki disease

Pediatric Rheumatology ◽

10.1186/s12969-020-00461-6 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Takashi Inoue ◽

Shokei Murakami ◽

Kenji Matsumoto ◽

Akio Matsuda

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Combination Therapy ◽

Molecular Mechanisms ◽

Ivig Therapy ◽

Unknown Etiology ◽

High Dose ◽

Ivig Resistance ◽

Tnf Α ◽

Clinical Benefits

Abstract Background Kawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology. Recent clinical studies led to reappraisal of the usefulness of initial combination therapy of intravenous immunoglobulin (IVIG) plus a corticosteroid for patients with severe KD. However, the molecular mechanisms underlying the clinical benefits of that combination therapy remain unclear. Here, we used cultured human coronary artery endothelial cells (HCAECs), as a mimic of KD, to study the possible mechanisms responsible for the clinical benefits of adding a corticosteroid to standard IVIG therapy for patients with severe KD. Methods HCAECs were stimulated with TNF-α, IL-1α or IL-1β in the presence and absence of high-dose IgG and/or dexamethasone (DEX). The mRNA and protein concentrations for high-mobility group box-1 (HMGB1), IL-1α, IL-6 and granulocyte-colony stimulating factor (G-CSF) in the culture supernatants were measured by quantitative PCR (qPCR) and ELISA, respectively. Apoptosis was evaluated by the caspase 3/7 activities. Results DEX, but not IgG, significantly inhibited apoptosis caused by inflammatory stimuli, resulting in effective reduction of HMGB1 and IL-1α protein release by HCAECs. As previously reported, DEX or IgG alone significantly suppressed TNF-α-induced production of IL-6 and G-CSF and mRNA expression, but induction of those cytokines by IL-1 s (IL-1α and IL-1β) was resistant to high-dose IgG. Conclusions A corticosteroid can effectively inhibit the release of HMGB1 and IL-1α, which may be involved in IVIG resistance in KD. Since high-dose IgG does not have such beneficial anti-cytotoxic effects, adding a corticosteroid to standard IVIG therapy may help prevent the progression of IVIG resistance in KD.

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DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Cellular Physiology and Biochemistry ◽

10.1159/000488619 ◽

2018 ◽

Vol 46 (2) ◽

pp. 520-531 ◽

Cited By ~ 7

Author(s):

Yan Ding ◽

Lanlan Shan ◽

Wenqing Nai ◽

Xiaojun Lin ◽

Ling Zhou ◽

...

Keyword(s):

Endothelial Cells ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Gene Knockout ◽

Umbilical Vein ◽

Vascular Endothelial Cell ◽

Tube Formation ◽

Vascular Endothelial

Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.

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CD40Gene Polymorphisms Associated with Susceptibility and Coronary Artery Lesions of Kawasaki Disease in the Taiwanese Population

The Scientific World JOURNAL ◽

10.1100/2012/520865 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 20

Author(s):

Ho-Chang Kuo ◽

Mei-Chyn Chao ◽

Yu-Wen Hsu ◽

Ying-Chi Lin ◽

Ying-Hsien Huang ◽

...

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Systemic Vasculitis ◽

Recessive Model ◽

Unknown Etiology ◽

Nucleotide Polymorphisms ◽

Taiwanese Population ◽

Allelic Discrimination Assay ◽

Allelic Discrimination ◽

First Time

Background. Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. Our previous studies showed expression ofCD40ligand on CD4+ T cells correlated to the coronary artery lesion (CAL) and disease progress in KD. Other studies from Japan suggested the role ofCD40Lin the pathogenesis of CAL, and this might help explain the excessive number of males affected with KD but cannot be reproduced by Taiwanese population. This study was conducted to investigate theCD40polymorphism in KD and CAL formation.Methods. A total of 950 subjects (381 KD patients and 569 controls) were investigated to identify 2 tagging single-nucleotide polymorphisms (tSNPs) ofCD40(rs4810485 and rs1535045) by using the TaqMan allelic discrimination assay.Results. A significant association was noted with regards toCD40tSNPs (rs1535045) between controls and KD patients (P=0.0405, dominant model). In KD patients, polymorphisms ofCD40(rs4810485) showed significant association with CAL formation (P=0.0436, recessive model). Haplotype analysis did not yield more significant results between polymorphisms ofCD40and susceptibility/disease activity of KD.Conclusions. This study showed for the first time that polymorphisms ofCD40are associated with susceptibility to KD and CAL formation, in the Taiwanese population.

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Transcellular migration of leukocytes is mediated by the endothelial lateral border recycling compartment

Journal of Experimental Medicine ◽

10.1084/jem.20082745 ◽

2009 ◽

Vol 206 (12) ◽

pp. 2795-2808 ◽

Cited By ~ 125

Author(s):

Zahra Mamdouh ◽

Alexei Mikhailov ◽

William A. Muller

Keyword(s):

Endothelial Cell ◽

Adhesion Molecule ◽

Molecular Mechanisms ◽

Vascular Endothelial Cell ◽

Dependent Manner ◽

Vascular Endothelial ◽

Lateral Border ◽

Endothelial Surface ◽

Platelet Endothelial Cell Adhesion ◽

Intracellular Adhesion Molecule

Leukocyte migration across endothelial cell borders (paracellular) and through endothelial cells (transcellular) appear to be distinct processes. During paracellular migration, membrane from a parajunctional reticulum of interconnected vesicles, the endothelial lateral border recycling compartment (LBRC), moves to surround the leukocyte in a kinesin-mediated, microtubule-dependent manner. We show that transcellular migration likewise requires targeted trafficking of LBRC membrane. We show that in addition to platelet/endothelial cell adhesion molecule (PECAM; CD31), CD99 and junctional adhesion molecule A (JAM-A), but apparently not vascular endothelial cell–specific cadherin (cadherin 5, CD144), are components of the LBRC. During transcellular migration, LBRC membrane invests the transmigrating leukocyte. Intracellular adhesion molecule 1 (ICAM-1) on the apical endothelial surface is enriched around adherent leukocytes. Depolymerization of microtubules has no effect on ICAM-1 enrichment but blocks targeted trafficking of LBRC membrane and transcellular migration by >90%. Similar to their effects on paracellular transmigration, antibodies against PECAM or CD99, but not JAM-A, block transcellular migration. We conclude that similar molecular mechanisms promote both para- and transcellular migration.

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DC-SIGN(CD209) Promoter −336 A/G (rs4804803) Polymorphism Associated with Susceptibility of Kawasaki Disease

The Scientific World JOURNAL ◽

10.1100/2012/634835 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Hong-Ren Yu ◽

Wei-Pin Chang ◽

Lin Wang ◽

Ying-Jui Lin ◽

Chi-Di Liang ◽

...

Keyword(s):

Kawasaki Disease ◽

Adhesion Molecule ◽

Risk Allele ◽

Systemic Vasculitis ◽

Intercellular Adhesion Molecule ◽

Unknown Etiology ◽

High Dose ◽

Lectin Receptor ◽

Ivig Resistance ◽

Intracellular Adhesion Molecule

Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is the most effective therapy for KD to reduce the prevalence of coronary artery lesion (CAL) formation. Recently, the α2, 6 sialylated IgG was reported to interact with a lectin receptor, specific intracellular adhesion molecule-3 grabbing nonintegrin homolog-related 1 (SIGN-R1) in mice and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) in human, and to trigger an anti-inflammatory cascade. This study was conducted to investigate whether the polymorphism ofDC-SIGN(CD209) promoter −336 A/G (rs4804803) is responsible for susceptibility and CAL formation in KD patients using Custom TaqMan SNP Genotyping Assays. A total of 521 subjects (278 KD patients and 243 controls) were investigated to identify an SNP of rs4804803, and they were studied and showed a significant association between the genotypes and allele frequency of rs4804803 in control subjects and KD patients (P=0.004under the dominant model). However, the promoter variant ofDC-SIGNgene was not associated with the occurrence of IVIG resistance, CAL formation in KD. The G allele ofDC-SIGNpromoter −336 (rs4804803) is a risk allele in the development of KD.

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Incomplete Kawasaki disease in Egypt

Global Cardiology Science and Practice ◽

10.21542/gcsp.2017.24 ◽

2018 ◽

Vol 2017 (3) ◽

Author(s):

Hala M Agha ◽

Hala S Hamza

Keyword(s):

Kawasaki Disease ◽

Viral Infections ◽

Systemic Vasculitis ◽

Vascular Inflammation ◽

Clinical Findings ◽

Unknown Etiology ◽

Cervical Lymphadenitis ◽

Barr Virus ◽

Childhood Illnesses ◽

Epstein Barr

[first paragraph of article]Kawasaki disease (KD) is a hybrid condition at the junction of infectious diseases, immunology, rheumatology, and cardiology.1 KD is a systemic vasculitis of unknown etiology predominately affecting medium-sized vessels such as the coronary arteries, which mainly affects infants and children2. The disease itself may be the characteristic manifestation of a common pathway of immune-mediated vascular inflammation in genetically susceptible hosts3. Untreated KD may lead to the formation of coronary artery aneurysms and sudden cardiac death in children. The diagnosis of KD is based on the clinical features of fever of at least 5 days together with at least 4 or 5 other features including rash, bilateral conjunctival injection, changes in peripheral extremities, lymphadenopathy and oropharyngeal changes4. The diseases that must be differentiated from KD because of similar clinical findings include viral infections (measles, adenovirus, enterovirus, and Epstein-Barr virus), scarlet fever, staphylococcal scaled skin syndrome, toxic shock syndrome, polyarteritis nodosa, bacterial cervical lymphadenitis, and juvenile rheumatoid arthritis5,6. Because each of the symptoms commonly occurs in other childhood illnesses, the disease can be difficult to diagnose, especially in children who present with an incomplete form of the disease. KD has not been previously reported from Egypt and there are special challenges in recognizing complete KD in a country where physicians have limited experience with the disease. The diagnosis of incomplete KD is thus even more challenging in this setting.

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Identification of Differentially Expressed Genes and Long Noncoding RNAs Associated with Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2019/6078251 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Lu-Mei Chi ◽

Li-Ping Wang ◽

Dan Jiao

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Differentially Expressed Genes ◽

Molecular Mechanisms ◽

Noncoding Rnas ◽

Gene Expression Omnibus ◽

Long Noncoding Rnas ◽

Differentially Expressed ◽

Similar Treatment ◽

Blood Samples

Objectives. This study aims to determine differentially expressed genes (DEGs) and long noncoding RNAs (lncRNAs) associated with Parkinson’s disease (PD) using a microarray. Methods. We downloaded the microarray data GSE6613 from the Gene Expression Omnibus, which included 105 samples. We selected 72 samples comprising 22 healthy control blood samples and 50 PD blood samples for further analysis. Later, we used Limma to screen DEGs and differentially expressed lncRNAs (DElncRNAs) and estimated their functions by the Gene Ontology (GO). Besides, the competing endogenous RNA (ceRNA) network, including microRNAs, lncRNAs, and mRNAs, was constructed to elucidate the regulatory mechanism. Furthermore, we performed the KEGG pathway enrichment with mRNAs in the ceRNA regulatory network and constructed a final network, including pathways, mRNAs, microRNAs, and lncRNAs. Results. Overall, we obtained 394 DEGs, including 207 upregulated DEGs and 187 downregulated DEGs, and 7 DElncRNAs, including 2 upregulated DElncRNAs and 5 downregulated DElncRNAs. Insulin-like growth factor-1 receptor (IGF1R) was considerably enriched in the endocytosis pathway. In the ceRNA regulation network, IGF1R was the target of hsa-miR-133b and lncRNAs of XIST, and PART1 could also be the target of hsa-miR-133b. While the upregulated DEGs were enriched in the GO terms of the cytoskeleton, cytoskeletal part, and microtubule cytoskeleton, the downregulated DEGs were enriched in the immune response. PRKACA was markedly enriched in numerous pathways, including the MAPK and insulin signaling pathways. Conclusions. IGF1R, PRKACA, and lncRNA-XIST could be potentially involved in PD, and these diverse molecular mechanisms could support the development of the similar treatment for PD.

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Abstract 12638: Autophagy-mitophagy Induction Improves Cardiovascular Inflammation in a Murine Model of Kawasaki Disease Vasculitis

Circulation ◽

10.1161/circ.142.suppl_3.12638 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Stefanie Marek-iannucci ◽

Angela Gomez ◽

Debbie Moreira ◽

Malcolm Lane ◽

Rebecca Porritt ◽

...

Keyword(s):

Kawasaki Disease ◽

Excision Repair ◽

Systemic Vasculitis ◽

Unknown Etiology ◽

Recent Experimental Data ◽

Intermittent Fasting ◽

Autophagic Flux ◽

Clinical Genetic ◽

Mtdna Damage ◽

Mitochondrial Fractions

Kawasaki Disease (KD), an acute febrile illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children. Recent experimental data from mouse models, as well as clinical, genetic and transcriptome evidence from KD patients suggest a key role of the NLRP3-IL-1β pathway in the pathogenesis of KD. NLRP3 can be activated by mitochondrial (mt) DNA released in the setting of defective autophagy/mitophagy, but a potential role for autophagy/mitophagy in KD cardiovascular inflammation has not been determined. In the Lactobacillus casei cell wall extract (LCWE) mouse model of KD vasculitis, LCWE injection in WT mice results in coronary arteritis, aortitis and myocarditis, mimicking human KD. We found that expression of the autophagy/mitophagy markers Parkin and p62 was significantly higher in whole lysate and mitochondrial fractions of heart tissue of LCWE-injected mice than controls, indicating impaired autophagic flux and mitophagy. Parkin -/- mice developed significantly more LCWE-induced cardiovascular lesions than control mice, and treatment of WT mice with a GLP-1 receptor agonist, known to activate Parkin, significantly reduced LCWE-induced inflammation. LCWE-induced cardiovascular lesions were amplified in mice deficient in OGG1, a base excision repair protein sensitive to mtDNA damage. Finally, inhibiting autophagy with chloroquine exacerbated LCWE-induced KD vasculitis, whereas inducing autophagy by intermittent fasting decreased cardiovascular inflammation in the model. Altogether, our data suggest that impaired autophagy/mitophagy exacerbates KD and supports a role for mtDNA damage in the disease. These findings enhance our understanding of KD pathogenesis and may provide novel therapeutic targets.

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Crucial transcripts predict response to initial immunoglobulin treatment in acute Kawasaki disease

Scientific Reports ◽

10.1038/s41598-020-75039-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Zhimin Geng ◽

Jingjing Liu ◽

Jian Hu ◽

Ying Wang ◽

Yijing Tao ◽

...

Keyword(s):

Gene Expression ◽

Kawasaki Disease ◽

Clinical Response ◽

Cell Activation ◽

Myeloid Cell ◽

Gene Expression Omnibus ◽

Ivig Treatment ◽

Precise Diagnosis ◽

Acute Kawasaki Disease ◽

Immunoglobulin Treatment

Abstract Although intravenous immunoglobulin (IVIG) can effectively treat Kawasaki disease (KD), 10–20% of KD patients show no beneficial clinical response. Developing reliable criteria to discriminate non-responders is important for early planning of appropriate regimens. To predict the non-responders before IVIG treatment, gene expression dataset of 110 responders and 61 non-responders was obtained from Gene Expression Omnibus. After weighted gene co-expression network analysis, we found that modules positively correlated with the non-responders were mainly associated with myeloid cell activation. Transcripts up-regulated in the non-responders, IL1R2, GK, HK3, C5orf32, CXCL16, NAMPT and EMILIN2, were proven to play key roles via interaction with other transcripts in co-expression network. The crucial transcripts may affect the clinical response to IVIG treatment in acute KD. And these transcripts may serve as biomarkers and therapeutic targets for precise diagnosis and treatment of the non-responders.

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Identification and Interaction Analysis of Significant Genes and MicroRNAs in Pterygium

BioMed Research International ◽

10.1155/2019/2767512 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Siying He ◽

Hui Sun ◽

Yifang Huang ◽

Shiqi Dong ◽

Chen Qiao ◽

...

Keyword(s):

Differentially Expressed Genes ◽

Molecular Mechanisms ◽

Interaction Analysis ◽

Interaction Network ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Gene Expression Omnibus ◽

Functional Enrichment ◽

Differentially Expressed ◽

Differentially Expressed Mirnas

Purpose. MiRNAs have been widely analyzed in the occurrence and development of many diseases, including pterygium. This study aimed to identify the key genes and miRNAs in pterygium and to explore the underlying molecular mechanisms. Methods. MiRNA expression was initially extracted and pooled by published literature. Microarray data about differentially expressed genes was downloaded from Gene Expression Omnibus (GEO) database and analyzed with the R programming language. Functional and pathway enrichment analyses were performed using the database for Annotation, Visualization and Integrated Discovery (DAVID). The protein-protein interaction network was constructed with the STRING database. The associations between chemicals, differentially expressed miRNAs, and differentially expressed genes were predicted using the online resource. All the networks were constructed using Cytoscape. Results. We found that 35 miRNAs and 301 genes were significantly differentially expressed. Functional enrichment analysis showed that upregulated genes were significantly enriched in extracellular matrix (ECM) organization, while downregulated genes were mainly involved in cell death and apoptotic process. Finally, we concluded the chemical-gene affected network, miRNA-mRNA interacted networks, and significant pathway network. Conclusion. We identified lists of differentially expressed miRNAs and genes and their possible interaction in pterygium. The networks indicated that ECM breakdown and EMT might be two major pathophysiological mechanisms and showed the potential significance of PI3K-Akt signalling pathway. MiR-29b-3p and collagen family (COL4A1 and COL3A1) might be new treatment target in pterygium.

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