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MiR-124 attenuates angiogenesis via the p38/MAPK and PI3K/AKT signaling pathways in acute myocardial infarction

ABSTRACT: Due to its rapid onset and high mortality, acute myocardial infarction (AMI) is considered as one of the most fatal diseases among heart diseases. Therefore, exploring its potential pathogenesis and developing effective treatment approaches for AMI have become a research hotspot in the medical community. In the present study, clinical blood samples from patients with AMI were analyzed and the results showed that the expression of microRNA (miR)-124 was significantly increased in peripheral blood of patients with AMI compared with healthy subjects. In addition, miR-124 overexpression notably promoted the apoptosis of HUVECs and attenuated their proliferative ability. Based on these findings, RNA from HUVECs was extracted and sequenced to investigate the changes in the gene expression profile triggered by miR-124 overexpression. The upregulated genes were enriched in several signaling pathways such as PI3K/AKT, while the downregulated ones were mainly enriched in metabolic-related signaling pathways. Additionally, the chromosomal location analysis revealed that the differentially expressed genes (DEGs) were distributed in all chromosomes, except the Y sex chromosome. Furthermore, the characteristic profile of DEGs mediated by miR-124 overexpression was analyzed via Connectivity Map analysis. The analysis revealed that anisomycin and sanguinarine, two agonists of the p38/MAPK signaling pathway involved in the inhibition of angiogenesis, exerted the highest enrichment scores. Additionally, Gene Set Enrichment Analysis demonstrated that DEGs were mainly enriched in the PI3K/AKT signaling pathway, thus inhibiting angiogenesis. Collectively, the present results indicated that miR-124 overexpression could promote AMI by affecting angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180765 | GEO | 2021/07/27

REPOSITORIES: GEO

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Project description:Background: Angiogenesis is an essential step for tissue development and its dysregulation is associated with various diseases, including moyamoya disease. Among the regulators of angiogenesis, galectin-1 encoded by LGALS1, plays essential roles, but the underlying mechanisms need to be further expounded. In this study, we systematically investigated the potential targets of galectin-1 by silencing LGALS1 (siLGALS1) in human umbilical vein endothelial cells (HUVECs) and performing whole transcriptome sequencing (RNA-seq) experiments. We also integrated galectin-1-interacting RNA data to explore how galectin-1 regulates gene expression and alternative splicing. Results: By systematical analysis, we found siLGALS1 treatment significantly regulated 1451 differentially expressed genes (DEGs), including 604 up-regulated DEGs and 847 down-regulated DEGs. The down-regulated DEGs were significantly enriched in angiogenesis and inflammatory response pathways. The involved genes included CCL2, GJA5, CALCRL, ACKR3, HEY1, AQP1, CD34, ECM1, RAMP2, and SELP, which were also validated by RT-qPCR experiment. We also analyzed the dysregulated alternative splicing (AS) profile by siLGALS1, and found siLGALS1 had obvious bias for dysregulated AS types, preferring to promote exon skipping and intron retention, and inhibit cassette exon events. Interestingly, we found the regulated AS genes (RASGs) were enriched in focal adhesion and VEGF signaling pathway, which were highly related to angiogenesis. Finally, we found hundreds of RASGs were also bound by galectin-1 using the published iRIP-seq data of galectin-1, including RASGs from angiogenesis pathway. Conclusions: In summary, our results demonstrated that galectin-1 could regulate angiogenesis-related genes at transcriptional and post-transcriptional levels, which is associated its RNA binding ability in HUVECs. The discovery extends our understanding on the functions and molecular mechanisms of galectin-1 during the development of angiogenesis, which could be served as a therapeutic option in anti-angiogenic treatment in future.

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MiR-124 attenuates angiogenesis via the p38/MAPK and PI3K/AKT signaling pathways in acute myocardial infarction

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