• IRF4
• artesunate
• macrophages
• neointimal hyperplasia
• restenosis

• Animals
• Artesunate/pharmacology
• Artesunate/therapeutic use
• Macrophages/metabolism
• Macrophages/drug effects
• Interferon Regulatory Factors/metabolism
• Interferon Regulatory Factors/genetics
• Neointima/metabolism
• Neointima/drug therapy
• Neointima/pathology
• Hyperplasia/drug therapy
• Hyperplasia/metabolism
• Mice
• Kruppel-Like Factor 4
• Male
• Mice, Inbred C57BL
• Humans

• 92169211 National Natural Science Foundation of China
• National Natural Science Foundation of China

• diagnosis
• hsa-miR-21-5p
• hsa-miR-93-5p
• in-stent restenosis
• lower extremity atherosclerotic disease; prediction

• Humans
• MicroRNAs/blood
• MicroRNAs/genetics
• Stents/adverse effects
• Male
• Female
• Endovascular Procedures/adverse effects
• Lower Extremity/blood supply
• Lower Extremity/surgery
• Lower Extremity/pathology
• Aged
• Atherosclerosis/blood
• Atherosclerosis/surgery
• Middle Aged
• ROC Curve
• Biomarkers/blood

• R01 HL141933 NHLBI NIH HHS

• Chemerin 15 peptide
• Click chemistry
• In-stent restenosis
• Inflammation regulation
• Vascular stent

• Animals
• Hyperplasia
• Chemokines/metabolism
• Stents
• Humans
• Neointima/pathology
• Male
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/chemistry
• Intercellular Signaling Peptides and Proteins/pharmacology
• Peptides/pharmacology
• Peptides/chemistry
• Mice
• Cell Proliferation/drug effects
• Wound Healing/drug effects
• Immobilized Proteins/pharmacology
• Human Umbilical Vein Endothelial Cells/metabolism
• Human Umbilical Vein Endothelial Cells/drug effects

• Extracellular vesicles
• Osteoarthritis
• Single-cell RNA sequencing
• miRNA sequencing

• Humans
• Osteoarthritis, Knee/genetics
• Osteoarthritis, Knee/metabolism
• Osteoarthritis, Knee/pathology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Single-Cell Gene Expression Analysis
• Cartilage, Articular/metabolism
• Chondrocytes/metabolism
• Extracellular Vesicles/metabolism

• CRISPR/Cas9
• DNA methylation
• DNMT3a
• TET2
• atherosclerosis
• epigenetics
• microRNAs
• stem cell therapy

• Bioresorbable vascular scaffold
• Drug-eluting stent
• Rabbit iliac artery model
• Safety
• Strut thickness

• Animals
• Rabbits
• Everolimus
• Iliac Artery
• Absorbable Implants
• Coronary Angiography/methods
• Drug-Eluting Stents

• Korea Medical Device Development Fund
• Ministry of Education, Science and Technology

• endothelial
• inflammation
• nanomatrix
• pro-healing
• rabbit
• smooth muscle cell
• stent

• Animals
• Rabbits
• Drug-Eluting Stents
• Endothelial Cells/metabolism
• Stents
• Neointima
• Thrombosis/metabolism
• Inflammation/metabolism

• R44 DK109789 NIDDK NIH HHS
• R01 HL150887 NHLBI NIH HHS
• R43 NS110114 NINDS NIH HHS
• R01 HL163802 NHLBI NIH HHS
• R43 HL160311 NHLBI NIH HHS

• GEO
• ISR
• bioinformatics
• miRNA-mRNA regulatory network

• Diabetic wound
• Graphene oxide
• PDLLA-PEG-PDLLA
• PVT1
• miR-21-5p

To investigate the association between the perivascular adipose tissue (PVAT) fat attenuation index (FAI) derived from coronary computed tomography angiography (CCTA) and the prevalence of in-stent restenosis (ISR) in patients with coronary stent implantation.

A total of 117 patients with previous coronary stenting referred for invasive coronary angiography (ICA) were enrolled in this retrospective observational analysis. All patients underwent CCTA between July 2016 and November 2021. The deep learning-based (DL-based) method was used to analyze and measure the peri-stent FAI value. Additionally, the relationship between hematological and biochemical parameters collected from all the patients was also explored. The least absolute shrinkage and selection operator (LASSO) method was applied to the most useful feature selection, and binary logistic regression was used to test the association between the selected features and ISR. The predictive performance for ISR of the identified subgroups was evaluated by calculating the area under the curve (AUC) of receiver operator curves plotted for each model. The Pearson correlation coefficient was used to assess the correlation of peri-stent FAI values with degrees of ISR.

The peri-stent FAI values in the ISR group were significantly higher than those in the non-ISR group (−78.1 ± 6.2 HU vs. −87.2 ± 7.3 HU, p < 0.001). The predictive ISR features based on the LASSO analysis were peri-stent FAI, high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), and high-sensitivity c-reactive protein (hs-CRP), with an AUC of 0.849, 0.632, 0.620, and 0.569, respectively. Binary logistic regression analysis determined that peri-stent FAI was uniquely and independently associated with ISR after adjusting for other risk factors (odds ratio [OR] 1.403; 95% CI: 1.211 to 1.625; p < 0.001). In the subgroup analysis, the AUCs of the left anterior descending coronary artery (LAD), left circumflex coronary artery (LCx), and right coronary artery (RCA) stents groups were 0.80, 0.87, and 0.96, respectively. The Pearson's correlation coefficient indicated a term moderately correlation between ISR severity and peri-stent FAI values (r = 0.579, P < 0.001).

The peri-stent FAI can be used as an independently non-invasive biomarker to predict ISR risk and severity after stent implantation.

• computed tomography angiography (CTA)
• fat attenuation index (FAI)
• in-stent restenosis (ISR)
• perivascular adipose tissue (PVAT)
• stents

Stent-graft-induced inflammation is an independent risk factor for adverse aortic remodeling in aortic dissection. In this context, we asked that whether a methylprednisolone-loaded stent-graft could reduce inflammation and degradation.

First, a coaxial electrospinning technique was used to create a core-shell film with methylprednisolone encapsulated in the inner of poly (L-lactide-co-caprolactone) nanofibers for controllable drug release. Second, an in vitro study was conducted to evaluate the biocompatibility of the nanofiber meshes. Third, the porcine aortic dissection model was developed to investigate the therapeutic effects of the methylprednisolone-loaded stent-graft.

The results demonstrated that the nanofiber-coated film with a methylprednisolone-poly-caprolactone core layer and a poly (L-lactide-co-caprolactone) shell layer could effectively sustain drug release in vitro. In vivo study showed that the methylprednisolone-loaded stent-graft could reduce degradtion of aortic dissection by regulating inflammation.

Overall, the controllable drug release by coaxial nanofiber is a promising approach to alleviate aortic inflammation and promote aortic remodeling after stent-graft implantation.

The online version contains supplementary material available at 10.1186/s40824-022-00259-5.

Long noncoding RNA GAS5 (lnc‐GAS5) and its target microRNA‐21 (miR‐21) regulate blood lipid, macrophages, Th cells, vascular smooth muscle cells to participate in atherosclerosis, and related coronary heart disease (CHD). The study aimed to further explore the linkage of their circulating expressions with common biochemical indexes, stenosis severity and inflammatory cytokines in CHD patients.

Ninety‐eight CHD patients and 100 controls confirmed by coronary angiography were enrolled. Plasma samples were collected for lnc‐GAS5 and miR‐21 detection by reverse transcription‐quantitative polymerase chain reaction and inflammatory cytokines determination by enzyme‐linked immunosorbent assay.

Lnc‐GAS5 was increased in CHD patients compared with controls (2.270 (interquartile range [IQR]: 1.676–3.389) vs. 0.999 ([IQR: 0.602–1.409], p < 0.001), whereas miR‐21 showed opposite tread (0.442 [IQR: 0.318–0.698] vs. 0.997 [IQR: 0.774–1.368], p < 0.001). In aspect of their intercorrelation, lnc‐GAS5 negatively linked with miR‐21 in CHD patients (p < 0.001) instead of controls (p = 0.211). Interestingly, among the common biochemical indexes, lnc‐GAS5 related to decreased high‐density lipoprotein cholesterol (p = 0.008) and increased C‐reactive protein (CRP) (p < 0.001), while miR‐21 correlated with lower total cholesterol (p = 0.024) and CRP (p < 0.001) in CHD patients. As stenosis degree, lnc‐GAS5 positively correlated with Gensini score (p < 0.001), but miR‐21 exhibited negative association (p = 0.003) in CHD patients. In terms of inflammatory cytokines, lnc‐GAS5 positively related to tumor necrosis factor α (TNF‐α) and interleukin (IL)‐17A, while miR‐21 negatively linked with TNF‐α, IL‐1β, IL‐6, and IL‐17 in CHD patients (all p < 0.05).

Circulating lnc‐GAS5 and its target miR‐21 exhibit potency to serve as biomarkers for CHD management.

• coronary heart disease
• inflammation
• lncrna GAS5
• microRNA-21
• stenosis severity

Bioresorbable scaffolds have emerged as a new generation of vascular implants for the treatment of atherosclerosis, and designed to provide a temporary scaffold that is subsequently absorbed by blood vessels over time. Presently, there is insufficient data on the biological and mechanical responses of blood vessels accompanied by bioresorbable scaffolds (BRS) degradation. Therefore, it is necessary to investigate the inflexion point of degradation, the response of blood vessels, and the pathophysiological process of vascular, as results of such studies will be of great value for the design of next generation of BRS. In this study, abdominal aortas of SD rats were received 3-D printed poly-l-actide vascular scaffolds (PLS) for various durations up to 12 months. The response of PLS implanted aorta went through two distinct processes: (1) the neointima with desirable barrier function was obtained in 1 month, accompanied with slow degradation, inflammation, and intimal hyperplasia; (2) significant degradation occurred from 6 months, accompanied with decreasing inflammation and intimal hyperplasia, while the extracellular matrix recovered to normal vessels which indicate the positive remodeling. These in vivo results indicate that 6 months is a key turning point. This “two-stage degradation and vascular characteristics” is proposed to elucidate the long-term effects of PLS on vascular repair and demonstrated the potential of PLS in promoting endothelium function and positive remodeling, which highlights the benefits of PLS and shed some light in the future researches, such as drug combination coatings design.

•

Proposed two-stage degradation of a PLLA BRS to reveal distinct neointimal recovery and vascular responsive processes.

• 3-D printing
• Bioresorbable scaffold
• Degradation behavior
• Functional endothelium
• Intravascular stents

• Pulmonary arterial hypertension
• Pulmonary artery smooth muscle cell
• Pulmonary vascular remodeling
• TGF-β1
• miR-663

• Aged
• Animals
• Becaplermin/pharmacology
• Cell Movement/drug effects
• Cell Movement/genetics
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• Cells, Cultured
• Disease Models, Animal
• Female
• Humans
• Male
• MicroRNAs/blood
• MicroRNAs/genetics
• Middle Aged
• Monocrotaline/toxicity
• Muscle, Smooth, Vascular/cytology
• Muscle, Smooth, Vascular/drug effects
• Pulmonary Arterial Hypertension/chemically induced
• Pulmonary Arterial Hypertension/genetics
• Pulmonary Arterial Hypertension/metabolism
• Pulmonary Artery/cytology
• Rats, Sprague-Dawley
• Smad2 Protein/metabolism
• Smad3 Protein/metabolism
• Transforming Growth Factor beta1/genetics
• Transforming Growth Factor beta1/metabolism
• Vascular Remodeling/drug effects
• Vascular Remodeling/genetics
• Rats

• microRNA
• polymorphism
• risk
• type 2 diabetes mellitus

Myocardial infarction (MI) is one of the most frequent cardiac emergencies, with significant potential for mortality. One of the major challenges of the post-MI healing response is that replacement fibrosis could lead to left ventricular remodeling (LVR) and heart failure (HF). This process involves canonical and non-canonical transforming growth factor-beta (TGF-β) signaling pathways translating into an intricate activation of cardiac fibroblasts and disproportionate collagen synthesis. Accumulating evidence has indicated that microRNAs (miRNAs) significantly contribute to the modulation of these signaling pathways. This review summarizes the recent updates regarding the molecular mechanisms underlying the role of the over 30 miRNAs involved in post-MI LVR. In addition, we compare the contradictory roles of several multifunctional miRNAs and highlight their potential use in pressure overload and ischemia-induced fibrosis. Finally, we discuss their attractive role as prognostic biomarkers for HF, highlighting the most relevant human trials involving these miRNAs.

• biomarker
• heart failure
• left ventricular remodeling
• miRNA
• myocardial infarction
• prognostic

Knowledge of stenosis in coronary arteries requires an understanding of the cellular and molecular processes that occur throughout the leukocyte rolling process. In this study, the roles of miR-125a-5p and miR-495-3p were investigated on the adhesion of endothelial cells (ECs) isolated from the human aorta.

Human primary endothelial cells were obtained from the aorta of people who had died of brain death. Whole blood was used to isolate the monocytes. The miR-125 and miR-495 were predicted and transfected into ECs using Poly Ethylene Imine (PEI). The expression levels of adhesion molecules and monocyte recruitment were identified by the RT-qPCR technique and Leukocyte-Endothelial Adhesion Assay kit, respectively.

The ICAM-1, ICAM-2 and VCAM-1 expression levels decreased significantly in the miR-495/PEI-transfected ECs (P < 0.05) while in the miR-125/PEI-transfected ECs only the ICAM-2 and ITGB-2 expression levels decreased significantly (P < 0.05) as compared to the miR-synthetic/PEI-transfected ECs. Furthermore, the monocyte adhesion was decreased in the miR-125 and miR-mix/PEI-transfected ECs as compared to the miR-synthetic/PEI-transfected ECs (P = 0.01 and P = 0.04, respectively).

According to the findings, the efficient relations between miR-125 and adhesion molecules may be responsible for the inhibition of monocyte rolling.

• Endothelial cell
• ICAM-1
• ICAM-2
• ITGB-2
• VCAM-1
• miR-125
• miR-495

Endovascular repair including percutaneous transluminal angioplasty (PTA) and stent implantation has become the standard approach for the treatment of peripheral arterial disease; however, restenosis is still the main limited complication for the long-term success of the endovascular repair. Endothelial denudation and regeneration, inflammatory response, and neointimal hyperplasia are major pathological processes occurring during in-stent restenosis (ISR). MicroRNAs exhibit great potential in regulating several vascular biological events in different cell types and have been identified as novel therapeutic targets as well as biomarkers for ISR prevention. This review summarized recent experimental and clinical studies on the role of miRNAs in ISR modification, with the aim of unraveling the underlying mechanism and potential therapeutic strategy of ISR.

• Coronary artery disease
• Target genes
• Transforming growth factor

Background: Vascular smooth muscle cells (VSMC) underwent phenotypic switching upon stimulation signals, and this is the prerequisite for their proliferation and migration. Previous work revealed that miR-455 may be involved in vascular stenosis. Thus, this study aimed to explore potential targets and mechanisms underlying the dynamics of miR-455 in vascular stenosis.

Methods: miR-455 and PTEN expression levels were studied in normal and stenosis tissue, as well as in VSMC in proliferation model. Manipulating miR-455 expression levels was achieved by transfection of either miR-455 mimic or inhibitor, and its effect on cell proliferation was studied by CCK-8 assay. Its effect on gene expression was studied by RT-qPCR and western blot. The expression regulation mechanism was studied by luciferase reporter system. Finally, the effect of miR-455 on regulating vascular stenosis was studied using a rat balloon-injured carotid artery stenosis model.

Results: High expression levels of miR-455 were detected in both stenosis arterial tissues and VSMC proliferation models. In contrast, the expression levels of PTEN were downregulated in these systems. miR-455 transfected VSMC showed higher levels of proliferation and decreased levels of PTEN. Potential binding sites between miR-455 and PTEN 3′UTR were predicted and confirmed. NF-kB p65 was found to bind directly on miR-455 promoter region and regulate its transcription. The progression of arterial stenosis could be delayed by introducing miR-455 antagomir.

Conclusions: The p65/miR-455/PTEN signaling pathway plays a crucial role in regulating VSMC proliferation and vascular stenosis. This indicated that miR-455 is a novel target that would help improve treatment outcomes in patients suffering from vascular stenosis.

• miR-455
• phenotype
• proliferation
• stenosis
• vascular smooth muscle cell

MicroRNA (miR) acts as a negative regulator of gene expression. Many literatures have suggested that miRs may be involved in the process of cell proliferation, inflammation, oxidative stress, energy metabolism and epithelial–mesenchymal transition. Thus, miRs may be implicated in the occurrence of non-small cell lung cancer (NSCLC). In the current investigation, we included 2249 subjects (1193 NSCLC patients and 1056 controls) and designed a study to identify the relationship of miR-146a rs2910164 C/G, -499a rs3746444 A/G and -196a-2 rs11614913 T/C with the risk of NSCLC. The risk factors (e.g., body mass index (BMI), sex, smoking, drinking and age) was used to adjust the odds ratios (ORs) and 95% confidence intervals (CIs). After conducting a power value assessment, we did not confirm that the miR-single nucleotide polymorphisms (SNPs) genotypic distributions were different in NSCLC cases and controls. However, the association of miR-196a-2 rs11614913 with a decreased risk of NSCLC was identified in the female subgroup (adjusted P=0.005, power = 0.809 for TC vs. TT, and adjusted P=0.004, power = 0.849 for CC/TC vs. TT). In addition, gene–gene interaction analysis showed that rs11614913 TC/3746444 AA and rs11614913 CC/rs3746444 AA could also reduce the susceptibility to NSCLC (rs11614913 TC/rs3746444 AA vs. rs11614913 TT/rs3746444 AA, P=0.001, power = 0.912 and rs11614913 CC/rs3746444 AA vs. rs11614913 TT/rs3746444 AA, P=0.003, power = 0.836). In conclusion, in overall comparisons, we did not confirm that the rs2910164, rs3746444, and rs11614913 SNPs genotypic distributions were different in NSCLC cases and controls. However, this case–control study demonstrates that miR-196a-2 rs11614913 may be a protective factor for the development of NSCLC among female patients.

• microRNA
• non-small cell lung cancer
• polymorphism
• susceptibility

The endothelial to mesenchymal transition (End–MT) can be associated with vascular calcification, by providing mesengenic progenitors. In this study, we investigated a link between End–MT and the osteogenic process and explored the involvement of miR-30a-5p and miR-30d as potential regulators of these processes. End–MT was induced in Human Umbilical Vein Endothelial Cells (HUVEC) through transforming growth factor-β1 (TGF-β1), TGFβ-3 and tumor necrosis factor-α (TNF-α), for 24 h and 6 days. End–MT mediators, mesenchymal and osteo/chondrogenic markers were analyzed through Real-Time PCR, immunofluorescence, flow cytometry and Western Blot. miR-30a-5p and miR-30d over-expression was carried out in HUVEC to explore their effects on End–MT and osteogenic differentiation. HUVEC at 24 h and 6 days gained mesenchymal morphology markers, including matrix metalloproteinase 9 (MMP-9), SLUG, VIMENTIN and α-smooth muscle actin (α-SMA), and a significant migratory potential, notably with TNF-α. After 6 days, the osteo/chondrogenic markers runt-related transcription factor 2 (RUNX-2) and SRY box transcription factor 9 (SOX-9) were upregulated. At this time point, miR-30a-5p and miR-30d decreased. Over-expression of miR-30a-5p and miR-30d affected End–MT mediators and the osteogenic potency in HUVEC, by reducing SLUG, VIMENTIN and RUNX-2. Our data suggest that End–MT represents a key link between inflammation and vascular calcification. Further, miR-30a-5p and miR-30d can regulate both the End–MT and the osteogenic processes, prompting future studies for exploring their potential use as therapeutic targets or biomarkers in vascular diseases.

• atherosclerosis
• calcification
• endothelial to mesenchymal transition
• inflammation
• micro-RNA
• osteogenic differentiation
• vascular injury

• extracellular vesicles
• heart injury
• inflammation
• ischemia‐reperfusion injury
• macrophage polarization
• miRNAs

• Aniline Compounds/pharmacology
• Animals
• Benzylidene Compounds/pharmacology
• Cytokines/metabolism
• Disease Models, Animal
• Extracellular Vesicles/drug effects
• Extracellular Vesicles/metabolism
• Heart Injuries/chemically induced
• Heart Injuries/metabolism
• Inflammation/metabolism
• Janus Kinase 2
• Macrophages/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs/metabolism
• Microscopy, Confocal
• Myocardial Ischemia/metabolism
• Myocardial Reperfusion Injury/chemically induced
• Myocardial Reperfusion Injury/metabolism
• STAT1 Transcription Factor/metabolism
• Signal Transduction

• M2 macrophage
• dedifferentiation
• exosomes
• intravascular stent
• stiffness
• vascular smooth muscle cell

• atherosclerosis
• carotid
• exosomes
• extracellular vesicles
• microRNA
• stroke

• Atherosclerosis
• Endothelial cells
• Macrophages
• Non-coding RNA
• Vascular smooth muscle cells
• microRNA

Peripheral artery disease (PAD) is a chronic condition characterized by inflammation. Emerging literature suggests that circulating exosomes and their microRNA (miRNA) contents may influence atherosclerosis and vascular remodeling. We hypothesize that circulating exosomes in patients with PAD directly modulate vascular cell phenotype and contain proinflammatory miRNAs.

Exosomes (particle size, 30-150 nm) were isolated from plasma of healthy individuals (n = 6), patients with mild PAD (mPAD; median Rutherford class, 2.5; n = 6), and patients with severe PAD (sPAD; median Rutherford class, 4; n = 5). Exosome identity, size, and concentration were determined by Western blot and nanoparticle tracking analysis. Human vascular smooth muscle cell (VSMC) and endothelial cell (EC) migration was assessed by a standard wound closure assay after exposure to exosome preparations. Monocyte-derived macrophages isolated from healthy volunteers were exposed to exosome preparations, and targeted gene expression was analyzed using quantitative polymerase chain reaction. Exosome miRNA cargos were isolated, and a panel of defined, vascular-active miRNAs was assessed by quantitative polymerase chain reaction.

There was no difference in overall exosome particle concentration or size between the three groups (one-way analysis of variance [ANOVA], P > .05). Compared with exosomes from healthy individuals, exosomes from mPAD and sPAD patients increased VSMC migration (1.0 ± 0.09-fold vs 1.5 ± 0.09-fold vs 2.0 ± 0.12-fold wound closure; ANOVA, P < .0001) and inhibited EC migration (1.8 ± 0.07-fold vs 1.5 ± 0.04-fold vs 1.3 ± 0.02-fold wound closure; ANOVA, P < .01) in a stepwise fashion. Exosomes also induced changes in monocyte-derived macrophage gene expression that did not appear PAD specific. Hierarchical analysis of exosome miRNA revealed distinct clustering of vascular-active miRNAs between the three groups. Several miRNAs that promote inflammatory pathways in vascular cells were expressed at higher levels in exosomes from sPAD patients.

Circulating exosomes from individuals with PAD exert in vitro functional effects on VSMCs and ECs that may promote adverse vessel remodeling. Exosomes from healthy individuals, mPAD patients, and sPAD patients contain distinct signatures of immune-regulatory miRNA. Together these data suggest that the proinflammatory cargo of circulating exosomes correlates with atherosclerosis severity in PAD patients and could influence vascular injury and repair.

Exosomes and their cargo have been implicated in several vascular remodeling processes including atherosclerosis, angiogenesis, and neointimal hyperplasia. In this study, we demonstrate that circulating exosomes from individuals with peripheral artery disease exert in vitro effects on vascular cells that may adversely affect vessel remodeling. Moreover, these exosomes contain elevated levels of vascular-active microRNA. Our results suggest that exosomes may serve as both biomarkers and effectors of vascular disease in patients with peripheral artery disease and motivate further investigation into the role of exosomes and their contents in aberrant remodeling in vascular diseases.

• Exosome
• Peripheral artery disease
• Restenosis
• Vascular remodeling
• miRNA

Numerous studies have highlighted that long noncoding RNA (lncRNA) can indirectly regulate the expression of mRNAs by binding to microRNA (miRNA). LncRNA-associated ceRNA networks play a vital role in the initiation and progression of several pathological mechanisms. However, the lncRNA-miRNA-mRNA ceRNA network in endothelial cells under cyclic stretch is seldom studied.

The miRNA, mRNA, and lncRNA expression profiles of 6 human umbilical vein endothelial cells (HUVECs) under circumferential stress were obtained by next-generation sequencing (NGS). We identified the differential expression of miRNAs, mRNAs, and lncRNAs using the R software package GDCRNATools. Cytoscape was adopted to construct a lncRNA-miRNA-mRNA ceRNA network. In addition, through GO and KEGG pathway annotations, we analyzed gene functions and their related pathways. We also adopted ELISA and TUNEL to investigate the effect of si-NEAT1 on endothelial inflammation and apoptosis.

We recognized a total of 32978 lncRNAs, 1046 miRNAs, and 31958 mRNAs in 6 samples; among them, 155 different expressed lncRNAs, 74 different expressed miRNAs, and 960 different mRNAs were adopted. Based on the established theory, the ceRNA network was composed of 13 lncRNAs, 44 miRNAs, and 115 mRNAs. We constructed and visualized a lncRNA-miRNA-mRNA network, and the top 20 nodes are identified after calculating their degrees. The nodes with most degrees in three kinds of RNAs are hsa-miR-4739, NEAT1, and MAP3K2. Functional analysis showed that different biological processes enriched in biological regulation, response to stimulus and cell communication. Pathway analysis was mainly enriched in longevity regulating, cell cycle, mTOR, and FoxO signaling pathway. Circumferential stress can significantly downregulate NEAT1, and after transducing si-NEAT1 for 24 h, inflammatory cytokine IL-6 and MCP-1 were significantly increased; furthermore, fewer TUNEL-positive cells were found in the si-NEAT1 treated group.

The establishing of a ceRNA network can help further understand the mechanism of vein graft failure. Our data demonstrated that NEAT1 may be a core factor among the mechanical stress factors and that cyclic stress can significantly reduce expression of NEAT1, give rise to inflammation in the early stage of endothelial dysfunction, and promote EC apoptosis, which may play an essential role in vein graft failure.

• number of stents
• percutaneous coronary intervention (pci)
• stent restenosis

• China/epidemiology
• Coronary Angiography
• Coronary Artery Disease/surgery
• Coronary Restenosis/epidemiology
• Coronary Restenosis/etiology
• Coronary Vessels/diagnostic imaging
• Coronary Vessels/surgery
• Female
• Follow-Up Studies
• Humans
• Incidence
• Male
• Middle Aged
• Percutaneous Coronary Intervention/methods
• Retrospective Studies
• Risk Factors
• Stents/statistics & numerical data

• coronary artery disease
• microRNA
• polymorphism
• risk

• Adhesion
• Atherosclerosis
• Dual specificity protein phosphatase 8
• Macrophage
• Migration
• microRNA-21

In this study, we designed a double layer-coated vascular stent of 316L stainless steel using an ultrasonic spray system to achieve both antiproliferation and antithrombosis. The coating included an inner layer of graphene oxide (GO) loaded with docetaxel (DTX) and an outer layer of carboxymethyl chitosan (CMC) loaded with heparin (Hep). The coated surface was uniform without aggregation and shedding phenomena before and after stent expanded. The coating treatment was able to inhibit the adhesion and activation of platelets and the proliferation and migration of smooth muscle cells, indicating the excellent biocompatibility and antiproliferation ability. The toxicity tests showed that the GO/DTX and CMC/Hep coating did not cause deformity and organ abnormalities in zebrafish under stereomicroscope. The stents with GO double-layer coating were safe and could effectively prevent thrombosis and in-stent restenosis after the implantation into rabbit carotid arteries for 4–12 weeks.

• drug coating
• graphene oxide
• restenosis
• thrombosis
• vascular stents

MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of multiple phases of atherothrombosis, and some reports have suggested altered levels in coronary artery in-stent restenosis (ISR). We recently demonstrated that miR-93-5 p was able to discriminate between patients with stable coronary artery disease (CAD) and those with no CAD, after adjusting for traditional risk factors (RFs). Thus, we wanted to determine if circulating miRNAs could predict coronary ISR.

To determine if circulating miRNAs have diagnostic capability for determining ISR in a cohort of matched patients with and without ISR.

To determine if miRNA plasma levels are elevated in coronary ISR, we conducted a study comprising 78 patients (39 with no ISR and 39 with ISR) and measured plasma miRNAs in each. We then determined the predictive ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) RFs, and stent length and diameter, to discriminate between ISR and no ISR. After correction for multiple testing, two miRNAs—miR425-5p and miR-93-5 p—were differential between patients with ISR and patients without ISR. Only miR-93-5 p remained a strong independent predictor of ISR after correction for FHS RFs (OR 6.30, p=0.008) and FHS RFs plus stent length and diameter (OR 4.80, p=0.02) and improved discriminatory power for ISR over FHS RFs alone in receiver operator characteristic curve analysis.

This novel finding that miR-93-5 p independently predicts ISR extends our recent observation that miR-93-5 p predicted CAD after adjustment for traditional CAD RFs. These data suggest further potential diagnostic utility.

• MicroRNA
• coronary stent
• restenosis

Objective: Abnormal proliferation or migration of vascular smooth muscle cells (VSMCs) can lead to vessel lesions, resulting in atherosclerosis and in stent-restenosis (IRS). The purpose of our study was to establish the role of miR-378a-5p and its targets in regulating VSMCs function and IRS.

Methods: EdU assays and Cell Counting Kit-8 (CCK-8) assays were applied to evaluate VSMCs proliferation, wound healing assays and transwell assays were applied to assess cells migration. Furthermore, quantitative reverse transcription–polymerase chain reaction (qRT-PCR) was performed to investigate the expression level of miR-378a-5p IRS patients and healthy individuals. Target genes were predicted using Target Scan and miRanda software, and biological functions of candidate genes were explored through bioinformatics analysis. Moreover, RNA-binding protein immunoprecipitation (RIP) was carried out to analyze the miRNAs interactions with proteins. We also used Immunofluorescence (IF) and fluorescence microscopy to determine the binding properties, localization and expression of miR-378a-5p with downstream target CDK1.

Results: The expression of miR-378a-5p was increased in the group with stent restenosis compared with healthy people, as well as in the group which VSMCs stimulated by platelet-derived growth factor-BB (PDGF-BB) compared with NCs. MiR-378a-5p over-expression had significantly promoted proliferative and migratory effects, while miR-378a-5p inhibitor suppressed VSMC proliferation and migration. CDK1 was proved to be the functional target of miR-378a-5p in VSMCs. Encouragingly, the expression of miR-378a-5p was increased in patients with stent restenosis compared with healthy people, as well as in PDGF-BB-stimulated VSMCs compared with control cells. Furthermore, co-transfection experiments demonstrated that miR-378a-5p over-expression promoted proliferation and migration of VSMCs specifically by reducing CDK1 gene expression levels.

Conclusion: In this investigatory, we concluded that miR-378a-5p is a critical mediator in regulating VSMC proliferation and migration by targeting CDK1/p21 signaling pathway. Thereby, interventions aimed at miR-378a-5p may be of therapeutic application in the prevention and treatment of stent restenosis.

• CDK1
• atherosclerosis
• miR-378a-5p
• migration
• proliferation
• stent-restenosis
• vascular smooth muscle cell

• biomarker
• miRNA expression and regulation
• passenger miRNA
• porcine vein graft and stent models
• smooth muscle cells
• vascular injury

• Animals
• Blood Vessels/drug effects
• Blood Vessels/injuries
• Blood Vessels/pathology
• Cytokines/pharmacology
• Gene Expression Regulation/drug effects
• Humans
• Intercellular Signaling Peptides and Proteins/pharmacology
• Male
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Muscle, Smooth, Vascular/pathology
• Myocytes, Smooth Muscle/drug effects
• Myocytes, Smooth Muscle/metabolism
• Swine

• RG/09/005/27915 British Heart Foundation

• miR-320
• migration
• neointimal formation
• proliferation
• vascular smooth muscle cell

Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21–null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-β1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-β1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-β1 secretion, was identified as a direct target of miR-21. miR-21–null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-β1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors.

MicroRNA-21 inhibition may convey its therapeutic benefits in fibrosis through its action in bone marrow cells rather than targeting fibroblasts directly.

• Cardiology
• Cell Biology
• Fibrosis
• Noncoding RNAs
• Platelets