Abstract
Obesity is a leading risk factor for type-2 diabetes. Diabetes often leads to the dysregulation of angiogenesis, although the mechanism is not fully understood. Previously, long noncoding RNAs (lncRNAs) have been found to modulate angiogenesis. In this study, we asked how the expression levels of lncRNAs change in endothelial cells in response to excessive palmitic acid treatment, an obesity-like condition. Bioinformatics analysis revealed that 305 protein-coding transcripts were upregulated and 70 were downregulated, while 64 lncRNAs were upregulated and 46 were downregulated. Gene ontology and pathway analysis identified endoplasmic reticulum stress, HIF-1 signaling, and Toll-like receptor signaling as enriched after palmitic acid treatment. Moreover, we newly report enrichment of AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling, and cysteine and methionine metabolism by palmitic acid. One lncRNA, Colorectal Neoplasia Differentially Expressed (CRNDE), was selected for further investigation. Palmitic acid induces CRNDE expression by 1.9-fold. We observed that CRNDE knockdown decreases endothelial cell proliferation, migration, and capillary tube formation. These decreases are synergistic under palmitic acid stress. These data demonstrated that lncRNA CRNDE is a regulator of endothelial cell proliferation, migration, and tube formation in response to palmitic acid, and a potential target for therapies treating the complications of obesity-induced diabetes.
Highlights
Diabetes and obesity have become major health problems throughout the world
LncRNA was considered expressed if the counts per million (CPM) in one condition was greater than 0.1 to include long noncoding RNAs (lncRNAs) expressed at low levels in the analysis as lncRNA expression levels are 10-fold less abundant than mRNAs16
All mRNAs or lncRNAs that were not found to be expressed were eliminated from the analysis. mRNAs and lncRNAs were considered as significantly differentially expressed if the fold change of palmitic acid versus control was greater than 1.5 or less than 0.66 and the p-value was less than 0.05
Summary
Diabetes and obesity have become major health problems throughout the world. As of 2017, approximately 24,710,000 people in the United States had diabetes, with an estimated economic impact of $327 billion[1]. A complete picture, has yet to be developed of how endothelial cells function and how they are regulated in obesity that lead to endothelial dysfunction, especially regarding the role of lncRNAs. LncRNAs are defined as RNA molecules that are longer than 200 nucleotides and do not code for protein. Palmitic acid can cause endothelial dysfunction by interfering with normal signaling pathways It impairs insulin signaling, eNOS activity, and nitric oxide production by inducing the activation of IκB-kinase β11 or promoting PTEN activity[12]. It was reported that palmitic acid treatment can activate the Stimulator of Interferon Genes (STING) by inducing mitochondrial damage and leakage of mitochondrial DNA into the cytosol[15] Despite these exciting studies, the transcriptome regulated by palmitic acid in endothelial cells and the role of lncRNAs in regulating endothelial response to palmitic acid are not completely understood. Knockdown of the lncRNA CRNDE inhibits angiogenic potential in endothelial cells
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