MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9 expression in oxLDL-stimulated monocyte/macrophages

ArticleinCardiovascular Research 83(1):131-9 · May 2009with24 Reads
DOI: 10.1093/cvr/cvp121 · Source: PubMed
Abstract
The inflammatory responses of monocytes/macrophages and the stimulation of lipid uptake into these cells by oxidized low density lipoprotein (oxLDL) are critical to the initiation and development of atherosclerosis. Increasing evidence has demonstrated that many microRNAs play important roles in the cell proliferation, apoptosis, and differentiation that accompany inflammatory responses. However, whether microRNAs are associated with monocyte/macrophage inflammatory responses or oxLDL stimulation is not yet known. The aim of the present study is to investigate microRNAs in monocytes/macrophages and their potential role in oxLDL-stimulation of lipid uptake and other atherosclerotic responses. Microarrays were used to analyse the global expression of microRNAs in oxLDL-stimulated human primary peripheral blood monocytes. Expression profiles of the microRNAs were verified using TaqMan real-time PCR. Five microRNAs (microRNA-125a-5p, microRNA-9, microRNA-146a, microRNA-146b-5p, and microRNA-155) were aberrantly expressed after oxLDL treatment of human primary monocytes. Bioinformatics analysis suggested that microRNA-125a-5p is related to a protein similar to ORP9 (oxysterol binding protein-like 9) and this was confirmed by a luciferase reporter assay. MicroRNA-125a-5p was found to mediate lipid uptake and to decrease the secretion of some inflammatory cytokines (interleukin-2, interleukin-6, tumour necrosis factor-alpha, transforming growth factor-beta) in oxLDL-stimulated monocyte-derived macrophages. MicroRNA-125a-5p may partly provide post-transcriptional regulation of the proinflammatory response, lipid uptake, and expression of ORP9 in oxLDL-stimulated monocyte/macrophages.
    • "It is known that the expression of miR-146a/b is increased in human atherosclerotic plaques [35], probably as a protective feedback mechanism, being known that miR-146 overexpression downregulates NF-κB activation that in turn reduces atherosclerosis [36]. Pro-inflammatory M1 macrophages exhibit an increased expression of miR-125a [37], which could also be a protective feedback mechanism, because the inhibition of the endogenous miR-125a levels in THP-1 macrophages increases the secretion of inflammatory cytokines and the expression of macrophage scavenger receptors resulting in increased lipid uptake [38]. The addition of glucose to the NG sera upregulated Drosha, DGCR8 and Dicer expression and further increased the miRNAs production in macrophages exposed to patients' sera. "
    [Show abstract] [Hide abstract] ABSTRACT: We aimed to determine the levels of microRNAs (miRNAs) in sera and HDL of acute coronary syndrome (ACS) compared to stable angina (SA) patients with/without hyperglycemia, and evaluate comparatively the functional effect of these sera on the processing machinery proteins (Drosha, DGCR8, Dicer) and miRNAs production in human macrophages. MiRNAs levels in sera and HDL from 35 SA and 72 ACS patients and 30 healthy subjects were measured by using microRNA TaqMan assays. MiR-223, miR-92a, miR-486, miR-122, miR-125a and miR-146a levels were higher in the hyperglycemic ACS compared to normoglycemic sera. MiR-223 and miR-486 prevailed in HDL2, while miR-92a predominated in HDL3, all three miRNAs discriminating between ACS and SA patients; their levels were increased in HDL from hyperglycemic ACS patients versus normoglycemic ones. The incubation of human macrophages with sera from ACS and SA patients showed that all patients’ sera induced an increase of Drosha, DGCR8 and Dicer expressions and of selected miRNAs levels compared to control sera, the effect being higher in the case of hyperglycemic versus normoglycemic ACS sera. The addition of glucose to SA and ACS sera increased Drosha, DGCR8 and Dicer expression and miRNAs levels in the exposed macrophages. In conclusion, hyperglycemia is associated with increased miR-223, miR-92a, miR-486 levels in HDL, which discriminate between ACS and SA patients. Exposure of human macrophages to ACS compared to SA sera determines the upregulation of Drosha, DGCR8 and Dicer expression and the increase of selected miRNAs production, the effect being augmented by an increased glucose concentration.
    Full-text · Article · Aug 2016
    • "In agreement with AGO2 suppression, most of the miRNA confirmed were suppressed in our database. In details, we confirmed the suppression of: 1) miR-146b-5p (over-expressed in human atherosclerotic plaques [32], and up-regulated in human monocytes/ macrophage stimulated with oxidized-LDL [33]); 2) the oncogenic [34] miR-19a-3p; 3) miR-181b-5p (involved in the modulation of inflammation and cancer [35]); 4) miR-107 (known to be suppressed by fatty acids, and associated to obesity, insulin resistance and fatty liver [36]); 5) miR-769-5p; 6) and miR-192-5p (that has been associated to the impairment in glucose metabolism, fatty liver, and acute myocardial in- farction [37,38]). Among up-regulated miRNAs, we were able to confirm the over-expression of only two miRNAs, namely the anti- inflammatory [39] miR-23b-3p and the tumor-suppressor [40,41] miR- 519b-3p (Fig. 4H and 4I). "
    [Show abstract] [Hide abstract] ABSTRACT: Extra virgin olive oil (EVOO) consumption has been associated with reduced cardiovascular risk but molecular mechanisms underlying its beneficial effects are not fully understood. Here we aimed to identify genes and miRNAs expression changes mediated by acute high- and low-polyphenols EVOO intake. Pre- and post-challenge gene and miRNAs expression analysis was performed on the peripheral blood mononuclear cells (PBMCs) of 12 healthy subjects and 12 patients with metabolic syndrome (MS) by using microarray and RT-qPCR. In healthy subjects, acute intake of EVOO rich in polyphenols was able to ameliorate glycaemia and insulin sensitivity, and to modulate the transcription of genes and miRNAs involved in metabolism, inflammation and cancer, switching PBMCs to a less deleterious inflammatory phenotype; weaker effects were observed in patients with MS as well as in healthy subjects following low-polyphenol EVOO challenge. Concluding, our study shows that acute high-polyphenols EVOO intake is able to modify the transcriptome of PBMCs through the modulation of different pathways associated with the pathophysiology of cardio-metabolic disease and cancer. These beneficial effects are maximized in healthy subjects and by the use of EVOO cultivars rich in polyphenols. Nutrigenomic changes induced by EVOO thus legitimate the well-known beneficial effects of EVOO in promoting human health and, potentially, preventing the onset of cardiovascular disease and cancer.
    Article · Jul 2016
    • "It is clear that miR-155 has a role in the differentiation of monocyte/macrophage subsets [10], and that it is highly expressed in activated immune system cells including macrophages subject to various stimuli [13,43] . Besides inflammatory stimuli, ox-LDL is capable of upregulating miR-155 in THP-1 macrophages [43]. Given that previous data for miR-155 activity have been collected using a variety of cells and mouse models, further studies with a more unified approach in terms of experimental strategy, should help to clarify the precise role of this microRNA in human atherosclerosis. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The angiotensin II type 2 receptor (AT2R) -1332 A/G polymorphism has been denoted as functional and associated with certain cardiovascular disease phenotypes. However, there are no studies considering the association of this gene polymorphism with carotid atherosclerosis (CA) and cerebrovascular events. Therefore, the aim of our study was to investigate a possible association of the AT2R -1332 A/G polymorphism with the occurrence of carotid plaques (CPs) and history of cerebrovascular insult (CVI) in advanced CA. Methods: The study group included 381 controls and 509 patients with CA consecutively admitted for endarterectomy. Genotyping was determined by polymerase chain reaction-restriction fragment length polymorphism method. The association was analyzed separately for males and females because the AT2R gene is located on the X chromosome. Results: The AT2R -1332 GG genotype was associated with the advanced CA in the female study group (recessive model of inheritance, AA+AG versus GG; adjusted odds ratio [OR] = 2.25; 95% confidence interval [CI] 1.17-4.33; P = .01). In the male subgroup of patients with CA, the significant overrepresentation of G/- hemizygote was detected in patients with CVI compared to male patients without this event (crude OR = 2.05, 95% CI 1.20-3.50, P = .008). Conclusions: This study suggests a gender-specific association between the AT2R -1332 A/G polymorphism and the occurrence of CP and the history of CVI in advanced CA, but further replication studies are needed.
    Full-text · Article · Apr 2016
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