Skip to main content
Download PDF
Download ePub

LncRNA MAGI2-AS3 promotes the progression of atherosclerosis by sponging miR-525-5p

Journal of Cardiothoracic Surgery volume 20, Article number: 206 (2025) Cite this article

Abstract

Background

Increasing evidence showed that lncRNAs are involved in the procession of atherosclerosis (AS). This study detected MAGI2-AS3 expression in the serum of AS patients and further investigated the mechanism of MAGI2-AS3 in AS.

Methods

MAGI2-AS3 and miR-525-5p in the AS patients’ serum and oxidized low-density lipoprotein (ox-LDL) induced human coronary artery smooth muscle cells (HCASMCs) were quantified by qRT-PCR. Spearman correlation was calculated between MAGI2-AS3 and clinical indexes or miR-525-5p. ROC curve analyzed the clinical diagnostic performance of MAGI2-AS3. Small interfering RNA targeting MAGI2-AS3 (si-MAGI2-AS3) silenced MAGI2-AS3 expression. HCASMCs proliferation, migration, and apoptosis were assayed by CCK-8, transwell, and flow cytometry, respectively. The target miR-525-5p was predicted by StarBase and verified by dual-luciferase reporter assay and co-transfection.

Results

MAGI2-AS3 increased in the AS patients’ serum and ox-LDL-induced HCASMCs. MAGI2-AS3 was negatively associated with C-reactive protein (CRP) and carotid intima-media thickness (CIMT). The ROC curve confirmed the efficacy of MAGI2-AS3 in distinguishing AS from control subjects. Silencing MAGI2-AS3 reversed the enhancement of proliferation and migration and the reduction of apoptosis caused by ox-LDL in HCASMCs. MiR-525-5p was predicted as a target and further verified by dual-luciferase assay. MiR-525-5p declined in both the serum of AS patients and ox-LDL-induced HCASMCs. Rescue experiments showed that miR-525-5p downregulation inverted the decrease in proliferation and migration, and the increase in apoptosis due to si-MAGI2-AS3 treatment.

Conclusions

In summary, our study demonstrated that MAGI2-AS3 participates in AS progression by sponging the miR-525-5p, indicating that MAGI2-AS3 may be a potential biomarker of AS.

Peer Review reports

Background

In recent years, the mortality of cardiovascular diseases (CVDs) has increased, causing a great burden on the global health system, and atherosclerosis (AS) is commonly recognized as the main reason for CVDs including coronary artery disease [1, 2]. The pathogenesis of AS involves multiple cell types and molecular interactions, including lipid accumulation, inflammation reactions, vascular endothelial cell damage, macrophage activation, and the alternations of vascular smooth muscle cell phenotype [3]. The series of interactions causes arterial lesions, intima plaques formation, and narrowing of the diameter, which eventually lowers blood flow and provokes CVDs [4]. The landscape of AS has changed and seems to affect younger individuals. With the aging population, the prevalence of AS is predicted to grow year by year [5]. Given the difficulty of early-stage diagnosis and poor prognosis, it is critical to explore high-risk populations and potential molecular mechanisms of AS progression [2, 6].

Over the decades, the study of noncoding RNA has become hot topic in research on multiple diseases. Long non-coding RNAs (lncRNAs) are produced by non-coding gene transcription lacking protein-coding capacity characterized by length over 200 bp [7]. In several decades, it has been proven that lncRNAs regulated gene expression by multiple approaches. For instance, lncRNAs can impact transcriptional and post-transcriptional regulation by enhancer-promoter looping, mRNA splicing, mRNA editing, protein translation, and protein modification. Additionally, lncRNAs could control mRNA stability by functioning as sponges that trap miRNAs [8]. Regulatory mechanisms of lncRNAs have been found in cellular reactions and cardiovascular disease through extensive studies and specific lncRNAs even act as biomarkers and drug targets [8, 9]. MAGI2 Antisense RNA 3 (MAGI2-AS3) is located on chromosome 7q21.11 and has been accepted as a participator in the neoplastic and non-neoplastic conditions. It could modulate cell proliferation, invasion, and migration to involve tumorigenesis [10]. A study showed that higher MAGI2-AS3 enhanced the capability of cell migration and invasion in gastric cancer [11]. Xu et al. revealed that MAGI2-AS3 regulates m6A methylation modification of MAGI2, playing an essential role in breast cancer [12]. Most of the studies on MAGI2-AS3 are in tumorigenesis while the gene regulatory network during the development of diseases is complex. We found that MAGI2-AS3 is associated with cardiac damage and tissue sclerosis in a related study [13], which aroused our interest. So far, no experimental studies have been found on MAGI2-AS3 in AS. miRNA. In the previous screening of target miRNAs, the studies indicated that miR-525-5p was downregulated in post-myocardial infarction myocardial cells [14], and its downregulation was linked to endothelial cell apoptosis [15]. Furthermore, miR-525-5p has been identified as a potential diagnostic marker in calcified aortic valve disease [16]. PCR verification in our experiments also revealed an inverse expression pattern between miR-525-5p and the MAGI2-AS3 of interest, suggesting that miR-525-5p may play a critical role in cardiovascular disease.

In this paper, we focus on the role of MAGI2-AS3 in the progression of AS. We detected the expression of MAGI2-AS3 in all subjects and assessed the relationship between MAGI2-AS and miR-525-5p. Furthermore, we reported the controlling of MAGI2-AS3 for the proliferation, migration, and apoptosis in HCASMCs in vitro. Our study aims to provide new evidence and insights for the clinical AS.

Methods

Clinical subjects

From 2021 to 2022, 216 subjects were recruited from Shanghai Baoshan Aged-Nursing Hospital Department of Cardiology involving 110 AS patients and 106 subjects without AS as the atherosclerosis group (AS) and healthy control group (HC), respectively. Blood samples were collected from all the subjects and centrifuged (3000 r/min, 10 min, 4℃) to obtain the serum. The baseline and measurements of the serum are shown in Table 1. Informed consent was signed by all subjects.

Table 1 Clinical characteristics of the subjects
Full size table

Patients met the following criteria: (1) one of the vessels over 50% according to coronary angiography; (2) carotid intima-media thickness (CIMT) between 0.9 and 1.2 mm, (3) no surgical history of coronary artery disease, and (4) no hematological system diseases, infection diseases, malignant tumors, or severe organ dysfunction.

Cell culture and treatment

Human Coronary Artery Smooth Muscle Cells (HCASMCs, 350–05 A) purchased from Sigma. RPMI-1640 medium (Gibco, USA) with 10% FBS (Gibco, Italy), 37℃, and 5% CO2 incubator were used to culture the cells. Oxidized low-density lipoprotein (ox-LDL) (UnionBiol, Beijing, China) was purchased to establish AS cell model [17,18,19], HCASMCs were seeded into 6-well plates (1 × 106 cells/well) and added with ox-LDL (0, 25, 50, 100 mg/L for 48 h) (Solarbio, Beijing, China). Given the significant increase of MAGI2-AS3 in 50 mg/L ox-LDL treatment, the next experiments were conducted on this condition.

Cell transfection

Small interfering RNA targeting MAGI2-AS3 (si-MAGI2-AS3), siRNA negative control (si-NC), miR-525-5p inhibitor, and negative control (miR-NC) were purchased by GenePharm (Shanghai, China). HCASMCs were seeded into 6-well plates (1 × 106 cells/well), then transfected with 50nM si-RNAs/inhibitor by Lipofectamine 2000 (Invitrogen) after treated with 50 mg/L ox-LDL for 48 h.

Cell proliferation, migration, and apoptosis

CCK-8 (Beyotime, Shanghai, China) was purchased to assay the proliferation. 4 × 103/well transfected cells were seeded into 96-well plates and subjected to 50 mg/L. 10μL CCK-8 was added and incubated for 3 h at different time points (0 h, 24 h, 48 h, 72 h). Optical density (OD) at 450 nm was detected to evaluate the cell proliferation activity by microplate reader (Bio-Rad, Hercules, CA, USA).

Transwell chamber (Corning, USA) was used to assay the cell migration. Transfected cells were seeded into the upper chamber (2 × 104/well, with FBS-free medium) of 24-well transwell plates. The basal chamber supplemented the same medium but containing 10% FBS for 24 h. The migratory potential was assayed by 0.1% crystal violet (Solarbio, China) to stain.

Annexin V-FITC Apoptosis Detection Kit (Beyotime, Shanghai, China) was purchased to assay the cell apoptosis. The transfected cell was collected after being stimulated with ox-LDL for 48 h. Cell suspension at 1 × 105/mL was prepared, then added fluorescent dye according to the manufacturer’s guidance. After incubation for 15 min, the apoptosis was measured by flow cytometry (FACSCalibur, BD, USA).

Dual-luciferase report assay

The bioinformatic tool StarBase (ENCORI) explored the potential binding site target of MAGI2-AS3. The dual-luciferase reporter assay confirmed the prediction. The wild type and mutant of MAGI2-AS3 fragment cloned into pmirGO vector by GenePharm (Shanghai, China) to construct WT-MAGI2-AS3 and MUT-MAGI2-AS3 plasmids. The plasmids were co-transfected with miRNAs for 48 h by lipofectamine 2000 (Invitrogen). The relative luciferase activity was estimated via the dual-luciferase reporter assay system (Promega, WI, USA).

qRT-PCR

RNA extraction used TRIzol reagent (Invitrogen) from cell/blood sample. Reverse transcription was performed by PrimeScript RT reagent kit (Takara, Dalian, China) to obtain the cDNA. PCR amplification reactions were executed by SYBR Premix Ex TaqII Kit (Takara). The relative expression was quantified by the method of 2−ΔΔCt and internal control of GAPDH or U6. Primer sequences were presented as follows: MAGI2-AS3, Forward, 5′-GCTATTGTCCTGCCCGTTAG-3′, Reverse, 5′-TCGTCAGGAGATCGAAGGTT-3′; miR-525-5p, Forward, 5′-GCGGTCCCTCTCCAAATGT-3′, Reverse, 5′- AGTGCAGGGTCCGAG GTATT-3′; U6, Forward, 5′-CTCGCTTCGGCAGCACA-3′, Reverse, 5′-AACGCTTCACGAATTTGCGT-3′; GAPDH, Forward, 5′-TGGCCTTCCGTGTTCCTAC-3′, Reverse, 5′-GAGTTGCTGTTGAAGTCGCA-3′.

Nuclear-cytoplasmic fractionation assay

Nuclear and cytoplasmic RNA from HCASMCs was extracted and isolated using the PARIS kit (Invitrogen) according to the manufacturer’s protocol. The relative expression of molecules in the nucleus and cytoplasm was detected by qPCR.

Bioinformatic analysis

The target genes of miR-525-5p were predicted based on online websites including miRDB, miRWalk, and StarBase. The intersection of the targets was selected using a venn diagram. GO and KEGG analysis was performed using R packages “clusterProfiler”. The online website STRING (https://string-db.org/) was used to analyze the protein-protein interaction (PPI) networks.

Statistical analysis

Experimental assays were conducted at least 3 times. All datasets were evaluated for normality and variance homogeneity. The Shapiro-Wilk test was used to confirm normality, and Levene’s test was applied to verify the homogeneity of variance. For comparisons between two groups, the Wilcoxon rank-sum test or unpaired Student’s t-test was used, depending on the data distribution. One-way ANOVA was employed for comparisons involving more than two groups. Statistical analyses were performed using R (version 4.4.0) and GraphPad Prism 9. Spearman correlation was evaluated for the relationship. The diagnostic value was analyzed using ROC curves. Results are presented as mean ± SD and P < 0.05 were significant (* P < 0.05, ** P < 0.01, *** P < 0.0001).

Results

MAGI2-AS3 was significantly increased in AS

The clinical features are presented in Table 1. Significant differences in CRP and CIMT were observed between the HC and AS groups, with both indexes being markedly higher in the AS group (Table 1, P < 0.05). Additionally, lncRNA MAGI2-AS3 was obviously upregulated in the serum of AS patients (Fig. 1A, P < 0.05). The diagnose value was assessed using the ROC curve, yielding an AUC of 0.876, a specificity of 0.802, and a sensitivity of 0.845, indicating superior distinguishing performance (Fig. 1B, P < 0.05). The Spearman association revealed a significant correlation between MAGI2-AS3 and clinical features, including CRP (Fig. 1C, P < 0.05) and CIMT (Fig. 1D, P < 0.05). To verify the change of expression, an AS model in vitro was established using ox-LDL in HCASMCs. The abundance of MAGI2-AS3 increased in a dose-dependent manner (Fig. 1E, P < 0.05). The 50 mg/L ox-LDL treatment, which led to clearly enhanced MAGI2-AS3 expression (Fig. 1E, P < 0.05), was used for further experiments.

Fig. 1
figure 1

MAGI2-AS3 markedly increased in AS. (A) Bar plot showed that the serum abundance of MAGI2-AS3 increased in AS patients (n = 106) compared to the HC group (n = 110). (B) ROC curve analysis indicated MAGI2-AS3 might serve as a diagnostic biomarker in AS. C, D. Spearman correlation between MAGI2-AS3 and CRP (C) or CIMT (D) was displayed. E. The abundance of MAGI2-AS3 increased with the addition of ox-LDL in ox-LDL HCASMCs (n = 5). Values were presented as mean ± SD. *P < 0.05, ***P < 0.001 vs. HC. AS, atherosclerosis; HC, healthy control; HCASMCs, human coronary artery smooth muscle cells; ROC, receiver operating characteristic

Full size image

MAGI2-AS3 influenced the HCASMCs proliferation, migration, and apoptosis

To figure out the impact of MAGI2-AS3 on cellular functions, the transfected with si-MAGI2-AS3 and 50 mg/L ox-LDL treatment were performed. The abundance of MAGI2-AS3 was suppressed by approximately 50% after transfection implying that the transfection was successful (Fig. 2A, P < 0.05). Under ox-LDL stimulation condition, si-MAGI2-AS3 significantly decreased the cell viability (Fig. 2B, P < 0.05) and migratory potential (Fig. 2C, P < 0.05) and increased the apoptosis (Fig. 2D, P < 0.05) compared with the control group in HCASMCs.

Fig. 2
figure 2

Down-regulated MAGI2-AS3 reversed the abnormal cellular functions caused by ox-LDL in HCASMCs. A. MAGI2-AS3 declined compared to the control group (50 mg/L ox-LDL treatment). B, C, D. Silencing MAGI2-AS3 decreased the cell proliferation (B) and migration (C), and increased cell apoptosis (D) compared to the control group (50 mg/L ox-LDL treatment). Values were presented as mean ± SD (n = 5). ***P < 0.001 vs. control. AS, atherosclerosis; HCASMCs, human coronary artery smooth muscle cells; ox-LDL, oxidized low-density lipoprotein

Full size image

MAGI2-AS3 sponged miR-525-5p in HCASMCs

Further experiments were conducted to explore the mechanism of MAGI2-AS3’s biological influence. Using the bioinformatic database Starbase, the potential target miR-525-5p and its binding sites were identified (Fig. 3A). The detection of the luciferase activity showed the opposite trend between miR-525-5p mimic and inhibitor treatments only in the WT-MAGI2-AS3 group (Fig. 3B, P < 0.05), verifying the predicted relationship by Starbase. RNA nuclear-cytoplasmic fractionation indicated that MAGI2-AS3 and miR-525-5p were predominantly located in the cytoplasm of HCASMCs (Fig. 3C).

Fig. 3
figure 3

MAGI2-AS3 served as sponge for miR-525-5p. A, B. The potential relationship between MAGI2-AS3 and miR-525-5p was obtained from StarBase (A) and further verified by dual-luciferase (n = 3) (B). C. The distribution of MAGI2-AS3, miR-525-5p, GAPDH, and U6 in the cytoplasmic and nuclear fractions of HCASMCs. D. The serum of miR-525-5p was reduced in AS patients. E. Spearman correlation between MAGI2-AS3 and miR-525-5p was displayed in scatter plot. F. The abundance of miR-525-5p decreased in a dose-dependent manner in ox-LDL-induced HCASMCs (n = 5). Values were presented as mean ± SD (n = 5). *P < 0.05, **P < 0.05, ***P < 0.001 vs. control. AS, atherosclerosis; HCASMCs, human coronary artery smooth muscle cells; ox-LDL, oxidized low-density lipoprotein

Full size image

Moreover, the serum of miR-525-5p was significantly downregulated in AS patients (Fig. 3D, P < 0.05). The Spearman association showed a negatively correlation between MAGI2-AS3 and miR-525-5p (Fig. 3E, P < 0.05). In contrast to MAGI2-AS3 expression, the miR-525-5p decreased markedly with the addition of ox-LDL dose (Fig. 3F, P < 0.05).

miR-525-5p downregulation reversed the influence of si-MAGI2-AS3 for cellular function

Next, a co-transfected assay supplemented with ox-LDL was performed in HCASMCs. The results showed MAGI2-AS3 abundance decreased and miR-525-5p abundance increased with si-MAGI2-AS3 treatment (Fig. 4A, P < 0.05). There was a downregulation in miR-525-5p after being treated with si-MAGI2-AS3 and miR-545-5p inhibitor (Fig. 4A, P < 0.05). In addition, co-treatment with si-MAGI2-AS3 and miR-545-5p inhibitor reversed the effects on HCASMCs proliferation (Fig. 4B, P < 0.05), migration (Fig. 4C, P < 0.05), and apoptosis (Fig. 4D, P < 0.05) compared to si-MAGI2-AS3 treatment alone.

Fig. 4
figure 4

Down-regulated miR-525-5p reversed the protective effects on cellular function due to si-MAGI2-AS3 under ox-LDL treatment (50 mg/L ox-LDL) in HCASMCs. A. The levels of MAGI2-AS3 and miR-525-5p after transfection. B, C, D. Co-transfected with si-MAGI2-AS3 and miR-525-5p inhibitor increased cell proliferation (B) and migration (C) and decreased the apoptosis (D) compared to transfection si-MAGI2-AS3 alone under ox-LDL treatment in HCASMCs. Values were presented as mean ± SD (n = 5). *P < 0.05, **P < 0.05, ***P < 0.001 vs. control. AS, atherosclerosis; HCASMCs, human coronary artery smooth muscle cells; ox-LDL, oxidized low-density lipoprotein

Full size image

GO, KEGG and PPI analysis

A total of 809, 14,490, and 1,596 target genes for miR-195-5p were predicted from miRDB, miRWalk, and StarBase, respectively, using the default parameters of each database. A total of 246 overlapping target genes were identified through a Venn diagram (Fig. 5A). GO enrichment analysis highlighted mRNA metabolism in biological processes, RNA-related granules in cellular components, and protein complex and enzyme activity in molecular functions (Fig. 5B). KEGG pathway analysis revealed enrichment in pathways related to cellular senescence, protein processing in the endoplasmic reticulum, longevity regulation, and liver and cancer-associated diseases (Fig. 5C). After increasing the interaction score to 0.9, PPI showed an intersection genes network including 24 genes (hid disconnected nodes, Fig. 5D).

Fig. 5
figure 5

Bioinformatic analysis of miR-525-5p target genes. A. Screen the targeted genes of miR-525-5p from miRDB, miRWalk, and StarBase. B, C. GO (B) and KEGG (C) enrichment pathways of targeted genes. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes. D. PPI Networks Functional Enrichment Analysis. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, protein-protein interaction

Full size image

Discussion

Previous experiments have found that MAGI2-AS3 influences the various malignancies. MAGI2-AS3 promotes colorectal cancer through activated proliferation and migration via the miR-3163/ TMEM106B axis [20]. The expression levels of MAGI2-AS3 were elevated in gastric cancer tissue [11], and patients with high MAGI2-AS3 abundance had significantly shorter overall survival compared to those with low expression levels [21]. In this study, we observed an abnormal increase of MAGI2-AS3 in the serum of AS patients. CIMT, assessed by ultrasonography, is a common independent risk factor for CVDs [22]. An increase in CIMT is closely related to the risk of CVDs [23] and might serve as a predictive marker for cardiovascular death in middle-aged individuals [24]. CRP plays a vital role not only in inflammation but also in AS [25]. Indeed, there is evidence supporting the correlation between CRP genotype and coronary events in elderly AS patients over 65 years old [26]. The increase in monomeric CRP content has been confirmed in atherosclerotic plaque [27]. In this paper, the abundance of MAGI2-AS3 was tightly associated with CIMT and CRP. Considering the expression of MAGI2-AS3 and the high performance of the ROC curve, all of the assays suggested that MAGI2-AS3 may play a significant biological role in AS.

Next, the experiments aimed to investigate the potential influence of MAGI2-AS3 in AS. The ox-LDL-induced cell model is extensively used for in vitro simulation of AS [17,18,19]. The abundance of MAGI2-AS3 increased with ox-LDL exposure, indicating that higher MAGI2-AS3 might be an impactful factor during the progression of AS. The occurrence and development of AS plaque is a gradual progress influenced by multiple elements [28]. HCASMCs proliferation and migration to the tunica intima are important steps leading to plaque formation. Excessive proliferation and suppressed apoptosis occur when a large number of HCASMCs reach tunica intima. The consequence is the synthesis of the extracellular matrix and the accumulation of lipids, which further leads to arterial fibrosis and thickening, narrowing the lemon. Additionally, HCASMCs apoptosis activates and stimulates inflammation, contributing to plaque development and rupture [29]. The AS cell model by ox-LDL induced accompanied with the aspects of cell injury and dysfunction such as inflammation, oxidative stress, proliferation, and apoptosis [2, 7]. Loss-of-function experiments showed that ox-LDL-induced increases in proliferation and migration, and decreases of apoptosis, were alleviated by silencing MAGI2-AS3. The detection of the HCASMCs indicated that the downregulation of MAGI2-AS3 plays a protective role in cell function. Based on these results, we speculated that target MAGI2-AS3 inhibition might be an underlying therapeutic approach.

Subsequently, the molecular mechanism of MAGI2-AS3 in AS was further explored. As negative regulators of gene expression, miRNAs participate in various physiological and pathological progresses that significantly influence CVDs [30, 31]. Sponging miRNAs is the most common way lncRNAs manage the expression of downstream mRNAs [32, 33]. StarBase predicted the binding sites between MAGI2-AS3 and miR-525-5p, and the target relationship was confirmed by luciferase activity. RNA functions are tightly linked to cellular location and we found that MAGI2-AS3 and miR-525-5p were predominantly localized to the cytoplasm. The abundance of miR-525-5p declined in both the serum of AS patients and the AS cell model. Furthermore, rescue experiments showed the reduction of miR-525-5p terminated the protective effects of si-MAGI2-AS3 on HCASMCs proliferation, migration, and apoptosis induced by ox-LDA. Based on these data, we proposed that miR-525-5p acts as a downstream miRNA of MAGI2-AS3. The PPI network analysis suggests several potential target genes for the miRNA, with FN1 standing out as particularly noteworthy. Previous studies have identified FN1 as a hub gene in myocardial infarction [34]. Multi-omics analyses indicate that FN1 plays a role in endothelial to mesenchymal transition [35], while combined bioinformatics and machine learning approaches have highlighted FN1 as a marker for aortic valve calcification [36]. These findings suggest that FN1 may be involved in the progression of atherosclerosis, making it a promising target for further investigation. However, this study only explored the impact of MAGI2-AS3 in the cell model, and potential downstream mRNA targets of miR-525-5p were not investigated. Although we performed enrichment analysis of potential downstream genes and attempted to identify relevant pathways, the database-based predictions were only preliminary. Further studies should consider the ex vivo and complete regulatory axis of MAGI2-AS3 to fully understand its mechanism. Additionally, the experimental approaches could be expanded. For example, in validating the interaction between RNAs, we will consider incorporating methods such as co-immunoprecipitation, RNA pull-down, and RIP assays. These techniques will further strengthen the integrity of the experiment and provide more comprehensive mechanistic insights.

Conclusions

In summary, this study verified that lncRNA MAGI2-AS3 was upregulated in AS patient serum and revealed that MAGI2-AS3 could affect the AS progression by targeting the miR-525-5p. This finding provides insights to explore the potential target for the therapeutic of AS.

Data availability

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Abbreviations

AS:

Atherosclerosis

CIMT:

Carotid intima-media thickness

CVDs:

Cardiovascular diseases

CRP:

C-reactive protein

HCASMCs:

Human coronary artery smooth muscle cells

lncRNAs:

Long non-coding RNAs

ox-LDL:

Oxidized low-density lipoprotein

si-MAGI2-AS3:

Small interfering RNA targeting MAGI2-AS3

References

  1. Vaduganathan M, Mensah GA, Turco JV, Fuster V, Roth GA. The global burden of cardiovascular diseases and risk: a compass for future health. J Am Coll Cardiol. 2022;80(25):2361–71. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jacc.2022.11.005

    Article  PubMed  Google Scholar 

  2. Tang X, Yin R, Shi H, Wang X, Shen D, Wang X, et al. LncRNA ZFAS1 confers inflammatory responses and reduces cholesterol efflux in atherosclerosis through regulating miR-654-3p-ADAM10/RAB22A axis. Int J Cardiol. 2020;315:72–80. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.ijcard.2020.03.056

    Article  PubMed  Google Scholar 

  3. Zhang X, Qin Y, Ruan W, Wan X, Lv C, He L, et al. Targeting inflammation-associated AMPK//Mfn-2/MAPKs signaling pathways by baicalein exerts anti-atherosclerotic action. Phytother Res. 2021;35(8):4442–55. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/ptr.7149

    Article  CAS  PubMed  Google Scholar 

  4. Zhen Z, Ren S, Ji H, Ding X, Zou P, Lu J. The LncRNA DAPK-IT1 regulates cholesterol metabolism and inflammatory response in macrophages and promotes atherogenesis. Biochem Biophys Res Commun. 2019;516(4):1234–41. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.bbrc.2019.06.113

    Article  CAS  PubMed  Google Scholar 

  5. Libby P. The changing landscape of atherosclerosis. Nature. 2021;592(7855):524–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s41586-021-03392-8

    Article  CAS  PubMed  Google Scholar 

  6. Xu J, Lu X, Shi G-P. Vasa vasorum in atherosclerosis and clinical significance. Int J Mol Sci. 2015;16(5):11574–608. https://doiorg.publicaciones.saludcastillayleon.es/10.3390/ijms160511574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhou Y, Zhang S, Ji W, Gan X, Hua L, Hou C, et al. LncRNA landscape of coronary atherosclerosis reveals differentially expressed LncRNAs in proliferation and migration of coronary artery smooth muscle cells. Front Cell Dev Biol. 2021;9:656636. https://doiorg.publicaciones.saludcastillayleon.es/10.3389/fcell.2021.656636

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zhang Z, Salisbury D, Sallam T. Long noncoding RNAs in atherosclerosis: JACC review topic of the week. J Am Coll Cardiol. 2018;72(19):2380–90. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jacc.2018.08.2161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Matsui M, Corey DR. Non-coding RNAs as drug targets. Nat Rev Drug Discov. 2017;16(3):167–79. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/nrd.2016.117

    Article  CAS  PubMed  Google Scholar 

  10. Yang G, Li T, Liu J, Quan Z, Liu M, Guo Y, et al. LncRNA MAGI2-AS3 suppresses castration-resistant prostate cancer proliferation and migration via the miR-106a-5p/RAB31 axis. Genomics. 2023;115(2):110599. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.ygeno.2023.110599

    Article  CAS  PubMed  Google Scholar 

  11. Li D, Wang J, Zhang M, Hu X, She J, Qiu X, et al. LncRNA MAGI2-AS3 is regulated by BRD4 and promotes gastric cancer progression via maintaining ZEB1 overexpression by sponging miR-141/200a. Mol Ther Nucleic Acids. 2020;19:109–23. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.omtn.2019.11.003

    Article  CAS  PubMed  Google Scholar 

  12. Xu X, Yuan X, Ni J, Guo J, Gao Y, Yin W, et al. MAGI2-AS3 inhibits breast cancer by downregulating DNA methylation of MAGI2. J Cell Physiol. 2021;236(2):1116–30. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/jcp.29922

    Article  CAS  PubMed  Google Scholar 

  13. Kortam MA, Elfar N, Shaker OG, El-Boghdady NA, Abd-Elmawla MA. MAGI2-AS3 and miR-374b-5p as putative regulators of multiple sclerosis via modulating the PTEN/AKT/IRF-3/IFN-β axis: new clinical insights. ACS Chem Neurosci. 2023;14(6):1107–18. https://doiorg.publicaciones.saludcastillayleon.es/10.1021/acschemneuro.2c00653

    Article  CAS  PubMed  Google Scholar 

  14. Zhang Y, Hou Y-M, Gao F, Xiao J-W, Li C-C, Tang Y. LncRNA GAS5 regulates myocardial infarction by targeting the miR-525-5p/CALM2 axis. J Cell Biochem. 2019;120(11):18678–88. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/jcb.29156

    Article  CAS  PubMed  Google Scholar 

  15. Zhu X, Chen B, Xu H. By modulating miR-525-5p/Bax axis, LINC00659 promotes vascular endothelial cell apoptosis. Immun Inflamm Dis. 2023;11(1):e764. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/iid3.764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zheng Y, Wen S, Jiang S, He S, Qiao W, Liu Y, et al. CircRNA/lncRNA-miRNA-mRNA network and gene landscape in calcific aortic valve disease. BMC Genomics. 2023;24(1):419. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12864-023-09441-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu X, Zheng X, Cheng J, Zhang K, Ma C. LncRNA TUG1 regulates proliferation and apoptosis by regulating miR-148b/IGF2 axis in ox-LDL-stimulated VSMC and HUVEC. Life Sci. 2020;243:117287. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.lfs.2020.117287

    Article  CAS  PubMed  Google Scholar 

  18. Liu X, Ma B-D, Liu S, Liu J, Ma B-X. Long noncoding RNA LINC00341 promotes the vascular smooth muscle cells proliferation and migration via miR-214/FOXO4 feedback loop. Am J Transl Res. 2019;11(3):1835–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang L, Zhou C, Qin Q, Liu Z, Li P. LncRNA LEF1-AS1 regulates the migration and proliferation of vascular smooth muscle cells by targeting miR-544a/PTEN axis. J Cell Biochem. 2019;120(9):14670–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/jcb.28728

    Article  CAS  PubMed  Google Scholar 

  20. Ren H, Li Z, Tang Z, Li J, Lang X. Long noncoding MAGI2-AS3 promotes colorectal cancer progression through regulating miR-3163/TMEM106B axis. J Cell Physiol. 2020;235(5):4824–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/jcp.29360

    Article  CAS  PubMed  Google Scholar 

  21. Zhang X, Jiang Y, Xie Y, Leng X, Song F. Comprehensive analysis of LncRNAs associated with the pathogenesis and prognosis of gastric cancer. DNA Cell Biol. 2020;39(2):299–309. https://doiorg.publicaciones.saludcastillayleon.es/10.1089/dna.2019.5161

    Article  CAS  PubMed  Google Scholar 

  22. Rui X, Wu X, Rong Z, Wang Z. Upgulation of LncRNA GASL1 inhibits atherosclerosis by regulating miR-106a/LKB1 axis. BMC Cardiovasc Disord. 2023;23(1):11. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12872-023-03038-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kumar P, Sharma R, Misra S, Kumar A, Nath M, Nair P, et al. CIMT as a risk factor for stroke subtype: a systematic review. Eur J Clin Invest. 2020;50(11):e13348. https://doiorg.publicaciones.saludcastillayleon.es/10.1111/eci.13348

    Article  PubMed  Google Scholar 

  24. Willeit P, Tschiderer L, Allara E, Reuber K, Seekircher L, Gao L, et al. Carotid intima-media thickness progression as surrogate marker for cardiovascular risk: meta-analysis of 119 clinical trials involving 100 667 patients. Circulation. 2020;142(7):621–42. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCULATIONAHA.120.046361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Stancel N, Chen C-C, Ke L-Y, Chu C-S, Lu J, Sawamura T, et al. Interplay between CRP, atherogenic LDL, and LOX-1 and its potential role in the pathogenesis of atherosclerosis. Clin Chem. 2016;62(2):320–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1373/clinchem.2015.243923

    Article  CAS  PubMed  Google Scholar 

  26. Lange LA, Carlson CS, Hindorff LA, Lange EM, Walston J, Durda JP, et al. Association of polymorphisms in the crp gene with circulating C-reactive protein levels and cardiovascular events. JAMA. 2006;296(22):2703–11.

    Article  CAS  PubMed  Google Scholar 

  27. Thiele JR, Habersberger J, Braig D, Schmidt Y, Goerendt K, Maurer V, et al. Dissociation of pentameric to monomeric C-reactive protein localizes and aggravates inflammation: in vivo proof of a powerful proinflammatory mechanism and a new anti-inflammatory strategy. Circulation. 2014;130(1):35–50. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCULATIONAHA.113.007124

    Article  CAS  PubMed  Google Scholar 

  28. Grootaert MOJ, Bennett MR. Vascular smooth muscle cells in atherosclerosis: time for a re-assessment. Cardiovasc Res. 2021;117(11):2326–39. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/cvr/cvab046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016;118(4):692–702. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.115.306361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang X, Rotllan N, Canfrán-Duque A, Sun J, Toczek J, Moshnikova A, et al. Targeted suppression of miRNA-33 using pHLIP improves atherosclerosis regression. Circ Res. 2022;131(1):77–90. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.121.320296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lu Y, Thavarajah T, Gu W, Cai J, Xu Q. Impact of MiRNA in atherosclerosis. Arterioscler Thromb Vasc Biol. 2018;38(9):e159–70. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/ATVBAHA.118.310227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu F, Deng W, Wan Z, Xu D, Chen J, Yang X, et al. LncRNA MAGI2-AS3 overexpression had antitumor effect on hepatic cancer via miRNA-23a-3p/PTEN axis. Food Sci Nutr. 2021;9(5):2517–30. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/fsn3.2199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tang C, Cai Y, Jiang H, Lv Z, Yang C, Xu H, et al. LncRNA MAGI2-AS3 inhibits bladder cancer progression by targeting the miR-31-5p/TNS1 axis. Aging. 2020;12(24):25547–63. https://doiorg.publicaciones.saludcastillayleon.es/10.18632/aging.104162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gao Y, Wang Y, Li M, Gao C. Bioinformatics analysis of potential common pathogenic mechanisms for systemic lupus erythematosus and acute myocardial infarction. Lupus. 2023;32(11):1296–309. https://doiorg.publicaciones.saludcastillayleon.es/10.1177/09612033231202659

    Article  CAS  PubMed  Google Scholar 

  35. Huang Q, Gan Y, Zheng X, Yu Z, Huang Q, Huang M. Uncovering endothelial to mesenchymal transition drivers in atherosclerosis via multi-omics analysis. BMC Cardiovasc Disord. 2025;25(1):104. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12872-025-04571-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xiong T, Han S, Pu L, Zhang T-C, Zhan X, Fu T, et al. Bioinformatics and machine learning methods to identify FN1 as a novel biomarker of aortic valve calcification. Front Cardiovasc Med. 2022;9:832591. https://doiorg.publicaciones.saludcastillayleon.es/10.3389/fcvm.2022.832591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

None.

Funding

No funding was received for conducting this study.

Author information

Author notes

  1. Lingfeng Zhu and Chan Yan are joint first author.

Authors and Affiliations

  1. Department of Cardiology, Shanghai Baoshan Aged-Nursing Hospital, No. 5425, Gonghexin Road, Baoshan District, Shanghai, 200443, China

    Lingfeng Zhu & Chan Yan

Authors
  1. Lingfeng Zhu
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Chan Yan
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Chan Yan analyzed and interpreted the patient data. Lingfeng Zhu was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lingfeng Zhu.

Ethics declarations

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the Shanghai Baoshan Aged-Nursing Hospital. Informed consent was signed by all subjects.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, L., Yan, C. LncRNA MAGI2-AS3 promotes the progression of atherosclerosis by sponging miR-525-5p. J Cardiothorac Surg 20, 206 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13019-025-03451-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13019-025-03451-5

Keywords

Journal of Cardiothoracic Surgery

ISSN: 1749-8090

Contact us