MiRNA-486 regulates angiogenic activity and survival of mesenchymal stem cells under hypoxia through modulating Akt signal

Shi, Xue; Wang, Hua; Xiao, Fengjun; Yin, Yue; Xu, Qinqin; Ge, Ri‐Li; Wang, Lisheng

doi:10.1016/j.bbrc.2016.01.084

Cited by 39 publications

(44 citation statements)

References 21 publications

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“…All samples were carefully selected for full term singleton pregnancies, non-complicated by maternal health conditions such as infection, which was necessary in reducing inter-sample variability. We observed that most of the up-regulated miRs regulated genes relevant to hypoxia responses [35–39], vascular disease [40–44], metabolism [45–49], inflammation [50–51], or were previously reported in pre-eclamptic placentas [52–55]. In contrast, the down-regulated miRs were for the most part relevant for genes with a role in obesity or cancers [56–58], though several had also been reported in association with pregnancy disorders involving placental insufficiency [52, 55,59–61].…”

Section: Resultsmentioning

confidence: 99%

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

et al. 2017

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Placental insufficiency leading to intrauterine growth restriction (IUGR) demonstrates perturbed gene expression affecting placental angiogenesis and nutrient transfer from mother to fetus. To understand the post-transcriptional mechanisms underlying such placental gene expression changes, our objective was to identify key non-coding microRNAs that express biological function. To this end, we initially undertook microarrays targeting microRNAs in a small sub-set of placentas of appropriate (AGA) versus small for gestational age (SGA) weight infants, and observed up-regulation of 97 miRs and down-regulation of 44 miRs in SGA versus AGA. In a larger cohort of samples (AGA, n = 21; SGA, n = 11; IUGR subset, n = 5), we validated by qRT-PCR differential expression of three specific microRNAs (miR-10b, -363 and -149) that target genes mediating angiogenesis and nutrient transfer. Validation yielded an increase in miR-10b and -363 expression of ~2.5-fold (p<0.02 each) in SGA versus AGA, and of ~3-fold (p<0.005) in IUGR versus AGA, with no significant change despite a trending increase in miR-149. To further establish a cause-and-effect paradigm, employing human HTR8 trophoblast cells, we assessed the effect of nutrient deprivation on miR expression and inhibition of endogenous miRs on target gene expression. In-vitro nutrient deprivation (~50%) increased the expression of miR-10b and miR-149 by 1.5-fold (p<0.02) while decreasing miR-363 (p<0.0001). Inhibition of endogenous miRs employing antisense sequences against miR-10b, -363 and -149 revealed an increase respectively in the expression of the target genes KLF-4 (transcription factor which regulates angiogenesis), SNAT1 and 2 (sodium coupled neutral amino acid transporters) and LAT2 (leucine amino acid transporter), which translated into a similar change in the corresponding proteins. Finally to establish functional significance we performed dual-luciferase reporter assays with 3’-insertion of miR-10b alone and observed a ~10% reduction in the 5’-luciferase activity versus the control. Lastly, we further validated by microarray and employing MirWalk software that the pathways and target genes identified by differentially expressed miRs in SGA/IUGR compared to AGA are consistent in a larger cohort. We have established the biological significance of various miRs that target common transcripts mediating pathways of importance, which are perturbed in the human IUGR placenta.

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Section: Resultsmentioning

confidence: 99%

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

et al. 2017

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“…Recent reports also provided evidence that miR-486 is upregulated during hypoxia and contributes to VEGF signaling in bone marrow-derived mesynechymal stem cells [93]. …”

Section: Micrornas - Regulation Of No Productionmentioning

confidence: 99%

Posttranscriptional and transcriptional regulation of endothelial nitric-oxide synthase during hypoxia: the role of microRNAs

et al. 2016

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Understanding the cellular pathways that regulate endothelial nitric oxide (eNOS, NOS3) expression and consequently nitric oxide (NO) bioavailability during hypoxia is a necessary aspect in the development of novel treatments for cardiovascular disorders. eNOS expression and eNOS-dependent NO cellular signaling during hypoxia promote an equilibrium of transcriptional and posttranscriptional molecular mechanisms that belong to both proapoptotic and survival pathways. Furthermore, NO bioavailability results not only from eNOS levels, but also relies on the presence of eNOS substrate and cofactors, the phosphorylation status of eNOS, and the presence of reactive oxygen species (ROS) that can inactivate eNOS. Since both NOS3 levels and these signaling pathways can also be a subject of posttranscriptional modulation by microRNAs (miRNAs), this class of short noncoding RNAs contribute another level of regulation for NO bioavailability. As miRNA antagomirs or specific target protectors could be used in therapeutic approaches to regulate NO levels, either by changing NOS3 mRNA stability or through factors governing eNOS activity, it is critical to understand their role in governing eNOS activity during hypoxa. In contrast to a large number of miRNAs reported to the change eNOS expression during hypoxia, only a few miRNAs modulate eNOS activity. Furthermore, impaired miRNA biogenesis leads to NOS3 mRNA stabilization under hypoxia. Here we discuss the recent studies that define miRNAs’ role in maintaining endothelial NO bioavailability emphasizing those miRNAs that directly modulate NOS3 expression or eNOS activity.

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“…MiR-486-5p has been identified in various cancer studies [169], and its serum concentration has been reported negatively correlated with systemic ventricular contractility following a cardiac bypass surgery [170]. More importantly, miR-486-5p has been associated with the angiogenesis process and was recently shown to regulate the cholesterol efflux from macrophages [171,172]. Literature about the association of miR-92a-3p and its related cluster with CVD is much more abundant and generally agrees with Niculescu's study [173,174].…”

Section: Lipoprotein-bound Mirnas As a Biomarkermentioning

confidence: 99%

microRNAs in lipoprotein and lipid metabolism: from biological function to clinical application

Desgagné

Bouchard

Guérin

2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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microRNAs (miRNAs) are short (~ 22 nucleotides), non-coding, single-stranded RNA molecules that regulate the expression of target genes by partial sequencespecific base-pairing to the targeted mRNA 3′UTR, blocking its translation, and promoting its degradation or its sequestration into processing bodies. miRNAs are important regulators of several physiological processes including developmental and metabolic functions, but their concentration in circulation has also been reported to be altered in many pathological conditions such as familial hypercholesterolemia, cardiovascular diseases, obesity, type 2 diabetes, and cancers. In this review, we focus on the role of miRNAs in lipoprotein and lipid metabolism, with special attention to the well-characterized miR-33a/b, and on the huge potential of miRNAs for clinical application as biomarkers and therapeutics in the context of cardiometabolic diseases.

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MiRNA-486 regulates angiogenic activity and survival of mesenchymal stem cells under hypoxia through modulating Akt signal

Cited by 39 publications

References 21 publications

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

Posttranscriptional and transcriptional regulation of endothelial nitric-oxide synthase during hypoxia: the role of microRNAs

microRNAs in lipoprotein and lipid metabolism: from biological function to clinical application

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