Dataset Information

MiR-302a Limits Vascular Inflammation by Suppressing Nuclear Factor-κ B Pathway in Endothelial Cells.

ABSTRACT: The inflammatory response of endothelial cells accelerates various vascular diseases. MicroRNAs (miRNAs) participate in diverse cellular processes during inflammation. In the present study, we found that miR-302a is an effective suppressor of vascular inflammation in endothelial cells. It was revealed that miR-302a exhibited a lower level in a lipopolysaccharide (LPS)-induced mouse model and in patients with vascular inflammatory disease. Genetic haploinsufficiency of miR-302 aggravated the LPS-induced vascular inflammatory response in mice, and overexpression of miR-302a attenuated vascular inflammation in mice. Furthermore, overexpression of miR-302a inhibited the synthesis and secretion of adhesion factors in endothelial cells, and suppressed the adhesion of monocytes to endothelium. In the study of molecular mechanism, we found that miR-302a relieved vascular inflammation mainly by regulating the nuclear factor kappa-B (NF-κB) pathway in endothelial cells. The results showed that interleukin-1 receptor-associated kinase4 (IRAK4) and zinc finger protein 91 (ZFP91) were the binding targets of miR-302a. MiR-302a prevented the nuclear translocation of NF-κB by inhibiting phosphorylation of IκB kinase complex β (IKKβ) and inhibitors of κBα (IκBα) via targeting IRAK4. In addition, miR-302a downregulated the expression of NF-κB by directly binding with ZFP91. These findings indicate that miR-302a negatively regulates inflammatory responses in the endothelium via the NF-κB pathway and it may be a novel target for relieving vascular inflammation.

SUBMITTER: Yuan JN

PROVIDER: S-EPMC8365611 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MiR-302a Limits Vascular Inflammation by Suppressing Nuclear Factor-κ B Pathway in Endothelial Cells.

Yuan Jia-Ni JN Hong Yu Y Ma Zhuo-Lin ZL Pang Rui-Ping RP Lei Qing-Qing QQ Lv Xiao-Fei XF Zhou Jia-Guo JG Huang Hui H Zhang Ting-Ting TT

Frontiers in cell and developmental biology 20210802

The inflammatory response of endothelial cells accelerates various vascular diseases. MicroRNAs (miRNAs) participate in diverse cellular processes during inflammation. In the present study, we found that miR-302a is an effective suppressor of vascular inflammation in endothelial cells. It was revealed that miR-302a exhibited a lower level in a lipopolysaccharide (LPS)-induced mouse model and in patients with vascular inflammatory disease. Genetic haploinsufficiency of miR-302 aggravated the LPS- ...[more]

PMID: 34409030

Similar Datasets

Project description:Silver nanoparticles (AgNP) are the dominant nanomaterials in commercial products and the medical field, but the widespread occurrence of AgNP has become a global threat to human health. Growing studies indicate that AgNP exposure can induce vascular endothelial toxicity by excessive oxidative stress and inflammation, which is closely related to cardiovascular disease (CVD), but the potential intrinsic mechanism remains poorly elucidated. Thus, it has been crucial to control the toxicological effects of AgNP in order to improve their safety and increase the outcome of their applications.Multiple researches have demonstrated that sodium selenite (Se) possesses the capability to counteract the toxicity of AgNP, but the functional role of Se in AgNP-induced CVD is largely unexplored. The aim of this study was to explore the potential protective effect of Se on AgNP-induced vascular endothelial lesion and elucidate the underlying mechanisms. An in vivo model of toxicity in animals was established by the instillation of 200 µL of AgNP into the trachea of rats both with (0.2 mg/kg/day) and without Se treated. In vitro experiments, human umbilical vein endothelial cells (HUVECs) were incubated with AgNP (0.3 µg/mL ) and Se for a duration of 24 h. Utilizing transmission electron microscopy, we observed that the internalization of AgNP-induced endothelial cells was desquamated from the internal elastic lamina, the endoplasmic reticulum was dilated, and the medullary vesicle formed. Se treatment reduced the levels of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), inhibited the release of pro-inflammatory cytokines (specifically tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), improved endothelial cell permeability, integrity, and dysfunction, and prevented damage to the aortic endothelium caused by AgNP. Importantly, we found that Se showed the capacity against AgNP with biological functions in guiding the intracellular reactive oxygen species (ROS) scavenging and meanwhile exhibiting anti-inflammation effects. Se supplementation decreased the intracellular ROS release and suppressed NOD-like receptor protein 3 (NLRP3) and nuclear factor kappa-B (NF-κB) mediated inflammation within AgNP-intoxicated rats and HUVECs. The anti-oxidant stress and anti-inflammatory effects of Se were at least partly dependent on nuclear factor erythroid 2-related factor 2 (Nrf2). Overall, our results indicated that the protectiveness of Se against AgNP-induced vascular endothelial toxicity injury was at least attributed to the inhibition of oxidative ROS and pro-inflammatory NF-κB/NLRP3 inflammasome by activating the Nrf2 and antioxidant enzyme (HO-1) signal pathway.

Project description:BackgroundIt is widely accepted that inflammation may contribute to cognitive impairment in patients with vascular dementia (VD). Our prior clinical researches have reported that acupuncture can alleviate cognitive function in VD, but the underlying mechanisms are still unclear. The purpose of this research was to explore whether acupuncture alleviates cognitive impairment by suppressing the microRNA-93- (miR-93-) mediated Toll-like receptor (TLR) signaling pathway, which triggers inflammatory responses in the central nervous system.MethodsVD was established by permanent bilateral common carotid artery occlusion in male Wistar rats. Three days after operation, the rats began daily treatment with acupuncture for two weeks. The levels of miR-93, Toll-like receptors (TLR2 and TLR4), intracellular signaling molecules (myeloid differentiation factor 88 (MyD88) and nuclear factor-kappa B (NF-κB)), and inflammatory cytokines were subsequently detected. TLR4 colocalized with neurons, microglia, and astrocytes in the hippocampus was evaluated. Neuroinflammation and cognitive function were determined after intracerebroventricular injection of TLR4 antagonist TAK-242 or agonist lipopolysaccharide (LPS) with or without acupuncture.ResultsWe found that acupuncture notably repressed the expression of inflammatory cytokines in the hippocampus and plasma of VD rats. The expression of TLR4, but not TLR2, was markedly downregulated by acupuncture, accompanied by a decrease in miR-93 and MyD88/NF-κB signaling pathway activation. The overexpression of TLR4 in microglia, but not in astrocytes and neurons, was reversed by acupuncture. Furthermore, intracerebroventricular injection of TAK-242 had similar effects to acupuncture on inflammation and cognitive function, while LPS injection abolished the beneficial effects of acupuncture.ConclusionsTaken together, these findings provide evidence that acupuncture attenuates cognitive impairment associated with inflammation through inhibition of the miR-93-mediated TLR4/MyD88/NF-κB signaling pathway in experimental VD. Acupuncture serves as a promising alternative therapy and may be an underlying TLR4 inhibitor for the treatment of VD.

Project description:BackgroundTrimethylamine-N-oxide (TMAO) has been proven to be a new proatherogenic compound for promoting inflammation and endothelial dysfunction. Hepatocyte-derived exosomes (Exos), including those derived from hepatocytes, play a pivotal role in the regulation of inflammation and endothelial function. As TMAO is produced in the liver, hepatocytes may be the potential target of TMAO. However, it is not yet clear whether TMAO can directly stimulate hepatocytes to produce Exos to mediate the detrimental effects of TMAO on vascular endothelial cells (VECs).MethodsHepatocytes treated with TMAO and Exos (TMAO-Exos) were isolated from the supernatant, and added to human aortic endothelial cells (HAECs). The expressions of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) were detected by quantitative polymerase chain reaction (qPCR). Cell apoptosis was evaluated using Hoechst 33342 staining and flow cytometry assay, and cell migration was assessed by scratch and transwell assay. C57BL/6 mice were treated with Exos for 24 h and the thoracic aortas were isolated, then the in vitro aortic ring bioassay was conducted to determine the changes of vasodilation. The expressions of cluster of differentiation 81, tumor susceptibility gene 101, nuclear factor-kappa B (NF-κB) p65, and Phospho-NF-κB p65 were detected by western blotting. The micro ribonucleic acid (miRNA) profiles of the Exos were then identified using RNA-sequencing and validated by qPCR. The miRNA-messenger RNA networks were constructed, and the biological functions of the target genes were annotated using bioinformatics methods.ResultsTMAO was found to stimulate hepatocytes to release Exos that could be taken up by HAECs, thus inducing inflammation and cell apoptosis, impairing cell migration, and inhibiting endothelium-dependent vasodilation. Additionally, the miRNAs such as miR-302d-3p carried by the TMAO-Exos were quite different to those in the TMAO-free group. A further analysis showed that the potential target genes for these miRNAs, such as mitogen-activated protein kinase 8, caspase 9 and BCL2-like 11, appeared to be involved with inflammation and endothelial function. Finally, we found that NF-κB signaling could be activated by TMAO-Exos.ConclusionsThese novel findings provide evidence that TMAO can indirectly talk to VECs by promoting hepatocytes to produce Exos that carry important genetic information.

Dataset Information

MiR-302a Limits Vascular Inflammation by Suppressing Nuclear Factor-κ B Pathway in Endothelial Cells.

Publications

MiR-302a Limits Vascular Inflammation by Suppressing Nuclear Factor-κ B Pathway in Endothelial Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets