Genome-wide differential expression profiling of lncRNAs and mRNAs in human induced pluripotent stem cell-derived endothelial cells exposed to e-cigarette extract

Hoai Huong Thi Le; Chen-Wei Liu; Philip Denaro 3rd; Jordan Jousma; Ning-Yi Shao; Irfan Rahman; Won Hee Lee

doi:10.1186/s13287-021-02654-6

Genome-wide differential expression profiling of lncRNAs and mRNAs in human induced pluripotent stem cell-derived endothelial cells exposed to e-cigarette extract

Stem Cell Res Ther. 2021 Dec 4;12(1):593. doi: 10.1186/s13287-021-02654-6.

Authors

Hoai Huong Thi Le¹, Chen-Wei Liu¹, Philip Denaro 3rd¹, Jordan Jousma², Ning-Yi Shao³, Irfan Rahman⁴, Won Hee Lee⁵

Affiliations

¹ Department of Basic Medical Sciences, University of Arizona College of Medicine, 425 N 5th Street, Building ABC1, Rm 426, Phoenix, AZ, 85004-2157, USA.
² Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612, USA.
³ Health Sciences, University of Macau, Macau, China.
⁴ Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.
⁵ Department of Basic Medical Sciences, University of Arizona College of Medicine, 425 N 5th Street, Building ABC1, Rm 426, Phoenix, AZ, 85004-2157, USA. whlee@arizona.edu.

Abstract

Background: Electronic-cigarette (e-cig) usage, particularly in the youth population, is a growing concern. It is known that e-cig causes endothelial dysfunction, which is a risk factor for the development of cardiovascular diseases; however, the mechanisms involved remain unclear. We hypothesized that long noncoding RNAs (lncRNAs) may play a role in e-cig-induced endothelial dysfunction.

Methods: Here, we identified lncRNAs that are dysregulated in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) following 24 h of e-cig aerosol extract treatment via microarray analysis. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analyses of the dysregulated mRNAs following e-cig exposure and constructed co-expression networks of the top 5 upregulated lncRNAs and the top 5 downregulated lncRNAs and the mRNAs that are correlated with them. Furthermore, the functional effects of knocking down lncRNA lung cancer-associated transcript 1 (LUCAT1) on EC phenotypes were determined as it was one of the significantly upregulated lncRNAs following e-cig exposure based on our profiling.

Results: 183 lncRNAs and 132 mRNAs were found to be upregulated, whereas 297 lncRNAs and 413 mRNAs were found to be downregulated after e-cig exposure. We also observed that e-cig caused dysregulation of endothelial metabolism resulting in increased FAO activity, higher mitochondrial membrane potential, and decreased glucose uptake and glycolysis. These results suggest that e-cig alters EC metabolism by increasing FAO to compensate for energy deficiency in ECs. Finally, the knockdown of LUCAT1 prevented e-cig-induced EC dysfunction by maintaining vascular barrier, reducing reactive oxygen species level, and increasing migration capacity.

Conclusion: This study identifies an expression profile of differentially expressed lncRNAs and several potential regulators and pathways in ECs exposed to e-cig, which provide insights into the regulation of lncRNAs and mRNAs and the role of lncRNA and mRNA networks in ECs associated e-cig exposure.

Keywords: e-cigarettes; endothelial dysfunction; fatty acid oxidation; iPSC-ECs; lncRNAs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

E-Cigarette Vapor* / adverse effects
Electronic Nicotine Delivery Systems*
Endothelial Cells / metabolism
Gene Expression Profiling
Gene Ontology
Gene Regulatory Networks
Humans
Induced Pluripotent Stem Cells* / metabolism
RNA, Long Noncoding* / genetics
RNA, Messenger* / genetics

Substances

E-Cigarette Vapor
RNA, Long Noncoding
RNA, Messenger