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.

NF-κB Pathway Related Long Non-Coding RNAs in Inflammatory Bowel Disease

“…In the CRC cell lines, RAD51-AS1 functioned as a competing endogenous RNA (ceRNA) for sponging miR-29b-3p and miR-29c-3p . An In vitro studies on miR-361-5p and miR-302a, results showed their inhibitory effect on the NF-κB signaling pathway [73,74].our studies also indicate a 2.465 fold overexpression in blood samples of UC patients compare to controls. Based on bioinformatics results, its instigating effect on NF-κB pathways maybe related to regulatory target miRNAs such as miR-361-5p and miR-302a.…”

The miR‐302/367 cluster: Aging, inflammation, and cancer

“…MiR-302 is involved in Treg differentiation that is aided by macromolecular proteins. 55 By targeting IL-1 receptor-associated kinase 4, MiR-302a reduces vascular inflammation by blocking nuclear factors in endothelial cells' nuclear translocation. This reduces the phosphorylation of kinase complex I and inhibitor.…”

“…This reduces the phosphorylation of kinase complex I and inhibitor. 55 Brain hemorrhage induces microglia activation and inflammatory cytokine release, leading to brain inflammation. In vivo investigations, adhesion molecules and inflammatory cytokines are increased in the absence of miR-367, whose expression is downregulated in the serum of patients with coronary heart disease.…”

“…When endothelial cells are abnormally activated, vascular inflammation is accelerated. MiR‐302 is involved in Treg differentiation that is aided by macromolecular proteins 55 . By targeting IL‐1 receptor‐associated kinase 4, MiR‐302a reduces vascular inflammation by blocking nuclear factors in endothelial cells' nuclear translocation.…”

Oxidative-Induced Angiogenesis Is Modulated by Small Extracellular Vesicle miR-302a-3p Cargo in Retinal Pigment Epithelium Cells

“…MiR-302 cluster inhibits angiogenesis by targeting VEGFA [33] and has also been involved in the reduction of vascular inflammation according to the binding sequence by interaction with zinc finger protein 91 (ZFP91). ZFP91 activates the hypoxia-induced factor 1α (HIF-1 α), promoting cell proliferation [34,35].…”