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Investigation of novel LPS-induced differentially expressed long non-coding RNAs in endothelial cells

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Abstract

The molecular mechanisms responsible for sepsis-induced endothelial dysfunction leading to an elevated risk of cardiovascular diseases remain undefined. Endotoxic or septic shock is a potentially lethal complication of systemic infection by Gram-negative bacteria. Lipopolysaccharide (LPS) is a critical glycolipid component of the outer wall of Gram-negative bacteria, and many of the sepsis-associated cellular signals by Gram-negative bacteria are attributed to LPS. Given that LPS has an established role in the pathophysiology of sepsis and long non-coding RNAs (lncRNAs) have been reported to critically regulate vascular homeostasis, a systematic transcriptional survey was conducted to evaluate the impact of LPS stimulation on human endothelial lncRNAs and protein-coding transcripts (mRNAs). LncRNAs and mRNAs from LPS-treated (100 ng/mL; 24 h) human umbilical vein endothelial cells (HUVECs) were profiled with the Arraystar Human lncRNA Expression Microarray V3.0. Of the 30,584 lncRNAs screened, 871 were significantly upregulated and 1068 significantly downregulated (p < 0.05) in response to LPS. In the same HUVEC samples, 733 of the 26,106 mRNAs screened were upregulated and 536 were downregulated. Among the differentially expressed lncRNAs, AL132709.5 was the most upregulated (~70 fold) and CTC-459I6.1 the most downregulated (~28 fold). Bioinformatics analyses indicated that the differentially expressed upregulated mRNAs are primarily enriched in cytokine–cytokine receptor interaction, infectious diseases, TNF signaling pathway, FoxO signaling pathway, and pathways in cancer. This is the first lncRNA and mRNA transcriptome profile of LPS-mediated changes in human endothelial cells. These observations may reveal novel endothelial targets of LPS that may be involved in the vascular pathology of sepsis.

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Abbreviations

CAMs:

Cell adhesion molecules

CVDs:

Cardiovascular diseases

CXCL6:

Chemokine, CXC motif, ligand 6

DE:

Differentially expressed

EGM-2:

Endothelial cell growth medium 2

EMT:

Epithelial–mesenchymal transition

ENCODE:

Encyclopedia of DNA Elements

GO:

Gene Ontology

HOTAIR:

HOX transcript antisense intergenic RNA

HOTTIP:

HOXA transcript at the distal tip

HULC:

Highly upregulated in liver cancer

HUVECs:

Human umbilical vein endothelial cells

KEGG:

Kyoto Encyclopedia of Genes and Genomes

lncRNAs:

Long non-coding RNAs

LPS:

Lipopolysaccharide

MALAT1:

Metastasis-associated lung adenocarcinoma transcript 1

mRNA:

Messenger RNA

ncRNAs:

Non-coding RNAs

NO:

Nitric oxide

PBS:

Phosphate-buffered saline

rRNA:

Ribosomal RNA

RASGRF2:

Ras protein-specific guanine nucleotide-releasing factor 2

TNF:

Tumor necrosis factor

tRNA:

Transfer RNA

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Acknowledgments

This work was supported by in part by grants from the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada to S. Verma. S. Verma is the Canada Research Chair in Atherosclerosis at the University of Toronto.

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Authors and Affiliations

  1. Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, 8th Floor, Bond Wing, 30 Bond Street, Toronto, ON, M5B 1W8, Canada

    Krishna K. Singh, Shoaib Muhammad, Adrian Quan, Vijay Gupta, Hwee Teoh & Subodh Verma

  2. Division of Vascular Surgery, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, 8th Floor, Bond Wing, 30 Bond Street, Toronto, ON, M5B 1W8, Canada

    Krishna K. Singh & Mohammed Al-Omran

  3. Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON, Canada

    Pratiek N. Matkar

  4. Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON, Canada

    Hwee Teoh

  5. Department of Surgery, University of Toronto, Toronto, ON, Canada

    Krishna K. Singh, Mohammed Al-Omran & Subodh Verma

  6. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Krishna K. Singh, Pratiek N. Matkar, Mohammed Al-Omran & Subodh Verma

  7. King Saud University-Li Ka Shing Collaborative Research Program, Department of Surgery, King Saud University, Riyadh, Kingdom of Saudi Arabia

    Mohammed Al-Omran

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  1. Krishna K. Singh
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  3. Shoaib Muhammad
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  8. Subodh Verma
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Electronic supplementary material

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11010_2016_2797_MOESM1_ESM.pdf

Supplementary Fig. 1. Quality assessment of RNAs, lncRNAs and mRNAs Data. A. Image of denaturing agarose gel (1 %) used to assess RNA integrity and genomic DNA contamination. The 28 s and 18 s rRNA bands were clear and intact. The larger rRNA (28 s) bands were more intense (almost double) in comparison to the corresponding lower rRNA (18 s) bands. The table shows the absorbance ratio for wavelengths 260 nm/280 nm and 260 nm/230 nm, concentration and the quantity of RNA used for array. B. Box-and-Whisker plots (10th, 90th percentile) showing normalized intensity for the 6 study samples to quickly visualize the distribution of our dataset. Mean intensity is denoted with a “+” sign. C1, C2 and C3 represent the control group, and L1, L2 and L3 represent the LPS (100 ng/mL)-treated group. (PDF 131 kb)

11010_2016_2797_MOESM2_ESM.pdf

Supplementary Fig. 2. Heat map and hierarchical clustering of differences in lncRNA and mRNA expression from HUVECs treated with LPS (100 ng/mL) vs. control. A, B. The dendrogram shows the relationships among the expression levels of samples. Hierarchical clustering that was performed based on ‘differentially expressed lncRNAs and mRNAs’, shows a distinguishable lncRNA and mRNA expression profiling among samples. (PDF 250 kb)

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Singh, K.K., Matkar, P.N., Muhammad, S. et al. Investigation of novel LPS-induced differentially expressed long non-coding RNAs in endothelial cells. Mol Cell Biochem 421, 157–168 (2016). https://doi.org/10.1007/s11010-016-2797-8

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  • DOI: https://doi.org/10.1007/s11010-016-2797-8

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