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MicroRNA-138 regulates hypoxia-induced endothelial cell dysfunction by targeting S100A1.

ABSTRACT: The Ca(2+) sensor S100A1 is essential for proper endothelial cell (EC) nitric oxide (NO) synthase (eNOS) activation. S100A1 levels are greatly reduced in primary human microvascular ECs subjected to hypoxia, rendering them dysfunctional. However mechanisms that regulate S100A1 levels in ECs are unknown. Here we show that ECs transfected with a S100A1-3' untranslated region (UTR) luciferase reporter construct display significantly reduced gene expression when subjected to low oxygen levels or chemical hypoxia. Bioinformatic analysis suggested that microRNA -138 (MiR-138) could target the 3'UTR of S100A1. Patients with critical limb ischemia (CLI) or mice subjected to femoral artery resection (FAR) displayed increased MiR-138 levels and decreased S100A1 protein expression. Consistent with this finding, hypoxia greatly increased MiR-138 levels in ECs, but not in skeletal muscle C2C12 myoblasts or differentiated myotubes or primary human vascular smooth muscle cells. Transfection of a MiR-138 mimic into ECs reduced S100A1-3 'UTR reporter gene expression, while transfection of an anti MiR-138 prevented the hypoxia-induced downregulation of the reporter gene. Deletion of the 22 nucleotide putative MiR-138 target site abolished the hypoxia-induced loss of reporter gene expression. Knockdown of Hif1-? mediated by siRNA prevented loss of hypoxia-induced reporter gene expression. Conversely, specific activation of Hif1-? by a selective prolyl-hydroxylase inhibitor (IOX2) reduced reporter gene expression even in the absence of hypoxia. Finally, primary ECs transfected with a MiR-138 mimic displayed reduced tube formation when plated onto Matrigel matrix and expressed less NO when stimulated with VEGF. These effects were reversed by gene transfer of S100A1 using recombinant adenovirus. We conclude that hypoxia-induced MiR-138 is an essential mediator of EC dysfunction via its ability to target the 3'UTR of S100A1.

SUBMITTER: Sen A

PROVIDER: S-EPMC3823839 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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MicroRNA-138 regulates hypoxia-induced endothelial cell dysfunction by targeting S100A1.

Sen Anagha A Ren Shumei S Lerchenmüller Carolin C Sun Jianxin J Weiss Norbert N Most Patrick P Peppel Karsten K

PloS one 20131111 11

The Ca(2+) sensor S100A1 is essential for proper endothelial cell (EC) nitric oxide (NO) synthase (eNOS) activation. S100A1 levels are greatly reduced in primary human microvascular ECs subjected to hypoxia, rendering them dysfunctional. However mechanisms that regulate S100A1 levels in ECs are unknown. Here we show that ECs transfected with a S100A1-3' untranslated region (UTR) luciferase reporter construct display significantly reduced gene expression when subjected to low oxygen levels or che ...[more]

PMID: 24244340

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Project description:Continuous activation of angiotensin II (Ang II) induces renal vascular endothelial dysfunction, inflammation and oxidative stress, all of which may contribute to renal damage. MicroRNAs (miRs/miRNAs) play a crucial regulatory role in the pathogenesis of hypertensive nephropathy (HN). The present study aimed to assess the differential expression profiles of potential candidate genes involved in Ang II-induced rat renal artery endothelial cell (RRAEC) dysfunction and explore their possible functions. In the present study, the changes in energy metabolism and autophagy function in RRAECs were evaluated using the Seahorse XF Glycolysis Stress Test and dansylcadaverine/transmission electron microscopy following exposure to Ang II. Subsequently, mRNA-miRNA sequencing experiments were performed to determine the differential expression profiles of mRNAs and miRNAs. Integrated bioinformatics analysis was applied to further explore the molecular mechanisms of Ang II on endothelial injury induced by Ang II. The present data supported the notion that Ang II upregulated glycolysis levels and promoted autophagy activation in RRAECs. The sequencing data demonstrated that 443 mRNAs and 58 miRNAs were differentially expressed (DE) in response to Ang II exposure, where 66 mRNAs and 55 miRNAs were upregulated, while 377 mRNAs and 3 miRNAs were downregulated (fold change >1.5 or <0.67; P<0.05). Functional analysis indicated that DE mRNA and DE miRNA target genes were mainly associated with cell metabolism (metabolic pathways), differentiation (Th1 and Th2 cell differentiation), autophagy (autophagy-animal and autophagy-other) and repair (RNA-repair). To the best of the authors' knowledge, this is the first report on mRNA-miRNA integrated profiles of Ang II-induced RRAECs. The present results provided evidence suggesting that the miRNA-mediated effect on the 'mTOR signaling pathway' might play a role in Ang II-induced RRAEC injury by driving glycolysis and autophagy activation. Targeting miRNAs and their associated pathways may provide valuable insight into the clinical management of HN and may improve patient outcome.

Dataset Information

MicroRNA-138 regulates hypoxia-induced endothelial cell dysfunction by targeting S100A1.

Publications

MicroRNA-138 regulates hypoxia-induced endothelial cell dysfunction by targeting S100A1.

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