miR-135a-5p overexpression in peripheral blood-derived exosomes mediates vascular injury in type 2 diabetes patients.
miR-135a-5p overexpression in peripheral blood-derived exosomes mediates vascular injury in type 2 diabetes patients.
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DOI：
10.3389/fendo.2023.1035029
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发表时间：
2023
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
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作者：
糖尿病病理学依赖于外泌体（Exos）。本研究探讨了外周血含外源性微小RNA（miRNA）如何导致2型糖尿病（T2 D）血管损伤。我们从GEO数据库的T2 D芯片数据中删除了DEmiRNA。我们从来自T2 D患者和15名健康对照的15份外周血样品中分离Exo，并测量Exo DEmiRNA水平。我们使用Geneards和mirWALK数据库查询的交集来查找T2 D外周血mRNA相关芯片靶基因。接下来，我们创建了STRING数据库候选靶基因相互作用网络图。接下来，我们使用ProfilerR软件包对T2 D相关的潜在靶基因进行GO和KEGG富集分析。最后，我们使用GSEA和PPI分析来选择T2 D血管损伤核心基因和信号通路。最后，我们使用HEK 293细胞进行荧光素酶测定，将T2 D外周血来源的Exo与HVSMC共培养，并检测HVSMC运动的改变。我们在GEO中发现了12个T2 D相关的DEmiRNA。通过qRT-PCR，T2 D患者来源的外周血Exo表现出显著上调的miR-135 a-3 p。接下来，我们预测了miR-135 a-3 p的下游靶mRNA，并筛选了715个DEmRNA，以创建调控网络图。通过GO功能和KEGG通路分析，DEmRNA对生物酶活性和血管内皮细胞的调节作用。ErbB信号通路差异突出。PPI网络研究表明，DEmRNA ATM基因调控ErbB信号通路。荧光素酶实验验证了miR-135 a-3 p和ATM靶标结合。T2 D患者来源的外周血Exo与HVSMC细胞的共培养增加HVSMC迁移、ErbB 2、Bcl-2和VEGF产生，并降低BAX和ATM。然而，miR-135 a-3 p可以逆转上述功能蛋白的产生并损害HVSMC细胞运动。T2 D患者来源的携带miR-135 a-3 p的外周血Exo进入HVSMC，可能靶向并抑制ATM，激活ErbB信号通路，促进HVSMC异常增殖和迁移，加重血管损伤。
Diabetes pathology relies on exosomes (Exos). This study investigated how peripheral blood Exo-containing microRNAs (miRNAs) cause vascular injury in type 2 diabetes (T2D). We removed DEmiRNA from T2D chip data from the GEO database. We isolated Exo from 15 peripheral blood samples from T2D patients and 15 healthy controls and measured Exo DEmiRNA levels. We employed the intersection of Geneards and mirWALK database queries to find T2D peripheral blood mRNA-related chip target genes. Next, we created a STRING database candidate target gene interaction network map. Next, we performed GO and KEGG enrichment analysis on T2D-related potential target genes using the ClusterProfiler R package. Finally, we selected T2D vascular damage core genes and signaling pathways using GSEA and PPI analysis. Finally, we used HEK293 cells for luciferase assays, co-cultured T2D peripheral blood-derived Exo with HVSMC, and detected HVSMC movement alterations. We found 12 T2D-related DEmiRNAs in GEO. T2D patient-derived peripheral blood Exo exhibited significantly up-regulated miR-135a-3p by qRT-PCR. Next, we projected miR-135a-3p’s downstream target mRNA and screened 715 DEmRNAs to create a regulatory network diagram. DEmRNAs regulated biological enzyme activity and vascular endothelial cells according to GO function and KEGG pathway analysis. ErbB signaling pathway differences stood out. PPI network study demonstrated that DEmRNA ATM genes regulate the ErbB signaling pathway. The luciferase experiment validated miR-135a-3p and ATM target-binding. Co-culture of T2D patient-derived peripheral blood Exo with HVSMC cells increases HVSMC migration, ErbB2, Bcl-2, and VEGF production, and decreases BAX and ATM. However, miR-135a-3p can reverse the production of the aforesaid functional proteins and impair HVSMC cell movement. T2D patient-derived peripheral blood Exo carrying miR-135a-3p enter HVSMC, possibly targeting and inhibiting ATM, activating the ErbB signaling pathway, promoting abnormal HVSMC proliferation and migration, and aggravating vascular damage.
影响因子：
3.7
作者：
Kim HS;Choi SI;Min HL;Kim MA;Kim WH
通讯作者：
Kim WH