MiR-486-5p inhibits eNOS and angiogenesis in cultured endothelial cells by targeting MAML3
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ABSTRACT:
PROVIDER: PRJNA1181906 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31221892.fastq.gz | Fastqsanger.gz | |||
| SRR31221893.fastq.gz | Fastqsanger.gz | |||
| SRR31221894.fastq.gz | Fastqsanger.gz | |||
| SRR31221895.fastq.gz | Fastqsanger.gz | |||
| SRR31221896.fastq.gz | Fastqsanger.gz |
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Project description:Kidney ischemia-reperfusion injury (IR) is associated with endothelial injury. Administration of miR-486-5p protects against rat kidney IR injury, with localization to capillary endothelial cells, although it inhibits IR-induced endothelial nitric oxide synthase (eNOS) protein expression. We studied the effects of miR-486-5p on eNOS and endothelial cell function and determined its mRNA targets. Methods: Human umbilical vein endothelial cells (HUVECs) were transfected with miR-486-5p and assayed for proliferation, migrartion, and network formation. Biotinylated miR-486-5p was transfected for pull-down of bound mRNA, followed by RNA sequencing. Results: miR-486-5p markedly decreased eNOS mRNA and protein in HUVECs, although eNOS mRNA was not found to be a direct target of miR-486-5p. miR-486-5p inhibited angiogenesis, which was rescued with eNOS plasmid transfection. RNA sequencing of biotinylated miR-486-5p pull-down RNA revealed highly significant enrichmenet in predicted targets FOXO1, FOXP1, TNFSF4, MAML3, and CELSR3, and in the non-predicted target SPCS2. RT-qPCR validated these transcripts as inhibited miR-486-5p. While silencing of FOXO1 had no impact on eNOS protein, MAML3 silencing inhibited eNOS levels. Conclusion: miR-486-5p inhibits angiogenesis in endothelial cells via down-regulation of eNOS, which involves selective targeting of MAML3. These data support a novel pathway regulating endothelial cell function.
2025-06-04 | GSE281065 | GEO
Project description:Background: Acute kidney injury (AKI) is a common clinical event with high morbidity and mortality. We previously demonstrated that injection of cord blood endothelial colony forming cell (ECFC)-derived exosomes, highly enriched in miRNA(miR)-486-5p, prevented ischemic kidney injury in mice. While preclinical models support involvement of several miRs in AKI, the direct effects of miR-486-5p on injury and the kidney transcriptome are unknown. Objective: We studied effects of miR-486-5p in mice with kidney ischemia-reperfusion (IR) injury, and compared the impact of miR-486-5p and ECFC-derived exosomes on the transcriptome of proximal tubules (PTs) and renal endothelial cells. Methods: Adult male mice were subjected to bilateral kidney ischemia (30 min), and injected via tail vein with or without vehicle, miR-486-5p mimic, ECFC-derived exosomes, or scramble miR at the start of reperfusion. Plasma and tissues were collected 24 hrs after reperfusion, and proximal tubular and endothelial cells were isolated for mRNA analysis by RNA-Seq. Results: In mice with kidney IR, injection of miR-486-5p mimic increased levels of miR-486-5p in proximal tubules and endothelial cells, and significantly improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis, compared to vehicle treatment. MiR-486-5p inhibited expression of phosphatase and tensin homolog (PTEN), and activated AKT. Similar results were observed with exosomes, but scramble miR had no effect. In proximal tubules, miR-486-5p or exosomes reduced expression of several AKI genes (e.g. Lcn2, Havcr1 and Krt20) and caused alterations in apoptotic genes compared to IR alone. In endothelium, miR-486-5p or exosomes caused milder effect than in PTs but still impacting on expression of injury-related genes. Conclusion: MiR-486-5p protects mice against ischemic kidney injury. Both miR-486-5p and exosomes reduce expression of apoptotic genes in PTs and endothelium. The results suggest that systemic delivery of miR-486-5p has therapeutic potential in ischemic AKI.
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Project description:MiRNAs have been shown to alter both protein expression and secretion in different cellular contexts. By combining in vitro, in vivo and in silico techniques, we demonstrated that overexpression of pre-miR-1307 reduced the ability of breast cancer cells to induce endothelial cell sprouting and angiogenesis. However, the molecular mechanism behind this and the effect of the individual mature miRNAs derived from pre-miR-1307 on protein secretion and is largely unknown. Here, we overexpressed miR-1307-3p|0, -3p|1 and 5p|0 in MDA-MB-231 breast cancer cells and assessed the impact of miRNA overexpression on protein secretion by Mass Spectrometry. Unsupervised hierarchical clustering revealed a distinct phenotype induced by overexpression of miR-1307-5p|0 compared to the controls and to the 5’isomiRs derived from the 3p-arm. Together, our results suggest different impacts of miR-1307-3p and miR-1307-5p on protein secretion which is in line with our in vitro observation that miR-1307-5p, but not the isomiRs derived from the 3p-arm reduce endothelial cell sprouting in vitro. Hence these data support the hypothesis that miR-1307-5p is at least partly responsible for impaired vasculature in tumors overexpressing pre-miR-1307.
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Project description:Peripheral nerve injury (PNI) results in loss of neural control and severe disabilities in patients. Promoting functional nerve recovery by accelerating angiogenesis is a promising neuroprotective treatment strategy. Here, we identified a bioactive Radix Astragalus polysaccharide (RAP) extracted from traditional Chinese medicine (TCM) as a potent enhancer of axonal regeneration and remyelination. Notably, RAP promoted functional recovery and delayed gastrocnemius muscle atrophy in a rat model of sciatic nerve crush injury. Further, RAP treatment induced angiogenesis in vivo. Moreover, our in vitro results showed that the role of RAP in endothelial cell (EC) migration and tube formation was probably related to the activation of AKT/eNOS signaling pathway. Altogether, our results show that RAP can enhance functional recovery by accelerating angiogenesis, thereby providing a polysaccharide-based therapeutic strategy for PNI.
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Project description:Effect of overexpression on miR-486-5p in Healthy doncor CD34+ cells
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Project description:MicroRNAs (miRNAs) are small non-coding RNAs that act as post-transcriptional gene modulators. Ginsenoside-Rg1, one of the active components of ginseng, has been confirmed by us as an angiogenesis inducer. Using miRNA microarray analysis, a total of 15 (including miR-214) and 3 miRNAs were found to be down- or up-regulated by Rg1 in human umbilical vein endothelial cells (HUVEC), respectively. Since miR-214 is closely related to endothelial nitric oxide synthase (eNOS) and hence angiogenesis; its expression was further validated by qRT-PCR. We also investigated the role of miR-214 on eNOS expression and in tubulogenesis of HUVEC by transfection of specific miRNA inhibitor or precursor. Our results suggested that Rg1 can down-regulate miR-214 expression in HUVEC, leading to an increase in eNOS expression which can promote angiogenesis. This result signifies a new understanding towards how a simple natural compound can affect physiological changes through modulation of miRNA expression. The study is used to investigate the role of miRNA-214 in Rg1-induced human endothelial cells.
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Project description:We report the effect of overexpression of miR-486-5pin heathy donors hematopoietic stem cells
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Project description:Endothelial nitric oxide synthase (eNOS) catalyzes the conversion of L-arginine and molecular oxygen into L-citrulline and nitric oxide (NO), a gaseous second messenger that influences cardiovascular physiology and disease. Several mechanisms regulate eNOS activity and function, including phosphorylation at Ser and Thr residues and protein-protein interactions. Combining a tandem affinity purification approach and mass spectrometry, we identified stromal cell-derived factor 2 (SDF2) as a component of the eNOS macromolecular complex in endothelial cells. SDF2 knockdown impaired agonist stimulated NO synthesis and decreased phosphorylation of eNOS at Ser1177, a key event required for maximal activation of eNOS. Conversely, SDF2 overexpression dose-dependently increased NO synthesis through a mechanism involving Akt and calcium (induced with ionomycin), which increased the phosphorylation of Ser1177 in eNOS. NO synthesis by iNOS (inducible NOS) and nNOS (neuronal NOS) was also enhanced upon SDF2 overexpression. We found that SDF2 was a client protein of the chaperone protein Hsp90, interacting preferentially with the M domain of Hsp90, which is the same domain that binds to eNOS. In endothelial cells exposed to vascular endothelial growth factor (VEGF), SDF2 was required for the binding of Hsp90 and calmodulin to eNOS, resulting in eNOS phosphorylation and activation. Thus, our data describe a function for SDF2 as a component of the Hsp90-eNOS complex that is critical for signal transduction in endothelial cells.
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Project description:Background: Hemorrhoids are common diseases of the anorectal system and are usually accompanied by vascular proliferation and edema. Curcumin is a natural molecule with potential anti-inflammatory, antitumor and antioxidant effects. This study aimed to explore the effect and molecular mechanism of curcumin in alleviating angiogenesis in rat hemorrhoids. Methods: A rat model of hemorrhoids was established via glacial acetic acid induction. Human venous endothelial cells were collected to perform cell experiments. The rats received curcumin at 25, 50, or 100 mg/kg/d. The rats were scored for perianal symptoms and inflammation levels, and the expression of angiogenesis-related factors was evaluated by immunofluorescence. Bioinformatics analysis, dual-luciferase, RT‒qPCR and Western blotting were used to verify the molecular mechanism of curcumin in the treatment of hemorrhoids. Results: Curcumin inhibited angiogenesis in endothelial cells and relieved the symptoms of hemorrhoids in rats. The study revealed that the expression of miR-190a-5p was significantly downregulated in hemorrhoids, whereas curcumin promoted the expression of miR-190a-5p. The results revealed that miR-190a-5p could inhibit angiogenesis and inflammation in endothelial cells by targeting TGFBR2, thereby alleviating the development of hemorrhoids. Mechanistically, curcumin inhibits the expression of TGFBR2 by upregulating miR-190a-5p, effectively blocking the angiogenesis ability of endothelial cells and thereby attenuating the progression and development of hemorrhoids in rats. Conclusion: Curcumin effectively inhibits angiogenesis in endothelial cells and relieves inflammation and the progression of hemorrhoids by regulating the miR-190a-5p/TGFBR2 molecular pathway.
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Project description:Erythroid-specific miR-451a and miR-486-5p are two dominant microRNAs (miRNAs) in human peripheral blood-derived small RNA sequencing libraries. Their overabundance reduces diversity as well as complexity of libraries after PCR amplification and consequently causes negative effects such as inaccurate detectability and quantification of other low abundant miRNAs. Here we present a cost-effective and feasible hybridization-based method to deplete these two erythropoietic miRNAs from blood-derived RNA samples
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