Sphingosine Kinase 1 Regulates the Pulmonary Vascular Immune Response

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Abstract

The aberrant proliferation of pulmonary artery smooth muscle (PASMCs) cells is a defining characteristic of pulmonary arterial hypertension (PAH) and leads to increased vascular resistance, elevated pulmonary pressure, and right heart failure. The sphingosine kinase 1 (SPHK1)/sphingosine-1 phosphate/sphingosine-1 phosphate receptor 2 pathway promotes vascular remodeling and induces PAH. The aim of this study was to identify genes and cellular processes that are modulated by over-expression of SPHK1 in human PASMCs (hPASMCs). RNA was purified and submitted for RNA sequencing to identify differentially expressed genes. Using a corrected p-value threshold of <0.05, there were 294 genes significantly up-regulated while 179 were significantly down-regulated. Predicted effects of these differentially expressed genes were evaluated using the freeware tool Enrichr to assess general gene set over-representation (enrichment) and ingenuity pathway analysis (IPA™) for upstream regulator predictions. We found a strong change in genes that regulated the cellular immune response. IL6, STAT1, and PARP9 were elevated in response to SPHK1 over-expression in hPASMCs. The gene set enrichment mapped to a few immune-modulatory signaling networks, including IFNG. Furthermore, PARP9 and STAT1 protein were elevated in primary hPASMCs isolated from PAH patients. In conclusion, these data suggest a role of Sphk1 regulates pulmonary vascular immune response in PAH.

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Next-generation sequencing technologies generate millions of short sequence reads, which are usually aligned to a reference genome. In many applications, the key information required for downstream analysis is the number of reads mapping to each genomic feature, for example to each exon or each gene. The process of counting reads is called read summarization. Read summarization is required for a great variety of genomic analyses but has so far received relatively little attention in the literature. We present featureCounts, a read summarization program suitable for counting reads generated from either RNA or genomic DNA sequencing experiments. featureCounts implements highly efficient chromosome hashing and feature blocking techniques. It is considerably faster than existing methods (by an order of magnitude for gene-level summarization) and requires far less computer memory. It works with either single or paired-end reads and provides a wide range of options appropriate for different sequencing applications. featureCounts is available under GNU General Public License as part of the Subread (http://subread.sourceforge.net) or Rsubread (http://www.bioconductor.org) software packages.

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Author and article information

Contributors

Roberto F. Machado:

ORCID: http://orcid.org/0000-0002-3722-5954

robmacha@iu.edu

Journal

Journal ID (nlm-ta): Cell Biochem Biophys

Journal ID (iso-abbrev): Cell Biochem Biophys

Title: Cell Biochemistry and Biophysics

Publisher: Springer US (New York )

ISSN (Print): 1085-9195

ISSN (Electronic): 1559-0283

Publication date (Electronic): 16 June 2021

Pages: 1-13

Affiliations

[1 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, , Indiana University School of Medicine, ; Indianapolis, IN USA

[2 ]GRID grid.412449.e, ISNI 0000 0000 9678 1884, Department of Clinical Pharmacology, School of Pharmacy, , China Medical University, ; Shenyang, Liaoning China

Author information

Yang Bai http://orcid.org/0000-0002-4420-4553

Angelia D. Lockett http://orcid.org/0000-0003-4966-1996

Robert S. Stearman http://orcid.org/0000-0002-7628-7066

Roberto F. Machado http://orcid.org/0000-0002-3722-5954

Article

Publisher ID: 1006

DOI: 10.1007/s12013-021-01006-8

PMC ID: 8206894

SO-VID: 42c93082-c791-4569-b31f-0983381074c8

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

History

Date accepted : 24 May 2021

Funding

Funded by: FundRef https://doi.org/10.13039/http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81803530-

Award Recipient : Yang Bai

Sphingosine Kinase 1 Regulates the Pulmonary Vascular Immune Response

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Abstract

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Vascular Biology

Most cited references 38

STAR: ultrafast universal RNA-seq aligner.

edgeR: a Bioconductor package for differential expression analysis of digital gene expression data

featureCounts: an efficient general purpose program for assigning sequence reads to genomic features.

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