MiR-4787-5p Regulates Vascular Smooth Muscle Cell Apoptosis by Targeting PKD1 and Inhibiting the PI3K/Akt/FKHR Pathway

Abstract

Vascular smooth muscle cell (VSMC) dysfunction is the main cause of aortic dissection (AD). In this study, we focused on the role and mechanism of miR-4787-5p in regulating VSMC apoptosis. Real-time fluorescence quantitative polymerase chain reaction was used to detect the expression of miR-4787-5p in aorta tissues of AD (n = 10) and normal aortic tissues of donors (n = 10). Cell apoptosis was tested by TUNEL assay and Annexin V FITC/PI staining flow cytometry. The expression of PC1 and the PI3K/Akt/ FKHR signaling pathway associated proteins in VSMCs was measured by Western blot. We found that the miR-4787-5p was highly expressed in aorta tissues of AD compared with 10 healthy volunteers. Meanwhile, PI3K/Akt/FKHR signaling pathway was inactive in the aortic tissue of AD. The overexpression of miR-4787-5p significantly induced VSMC apoptosis, and miR-4787-5p knockdown showed the opposite results. In addition, polycystic kidney disease 1 gene, which encodes polycystin-1 (PC1), was found to be a direct target of miR-4787-5p in the VSMCs and this was validated using a luciferase reporter assay. Overexpression of PC1 by a lentivirus packaging PC1-overexpression plasmid (LV-PC1) plasmids markedly eliminated the promotion of miR-4787-5p overexpression on VSMC apoptosis. Finally, it was found that miR-4787-5p deactivated the PI3K/Akt/FKHR pathway, as demonstrated by the down-regulation of phosphorylated (p-)PI3K, p-Akt, and p-FKHR. In conclusion, these findings confirm an important role for the miR-4787-5p/polycystic kidney disease 1 axis in AD pathobiology.

Identification of Key Immune Infiltration Related Genes Involved in Aortic Dissection Using Bioinformatic Analyses and Experimental Verification

“…[22][23][24] PI3K-Akt signaling plays an important role in phenotypic switching and apoptosis of human aortic vascular smooth muscle cells. [25][26][27] Those studies together with our results suggest that activated B cell-related DEGs may regulate the migration, apoptosis, and phenotype switch of smooth muscle cells to further affect the development of AD.…”

A hiPSC-derived lineage-specific vascular smooth muscle cell-on-a-chip identifies aortic heterogeneity across segments

“…Notably, expression levels of genes involved in PI3K/Akt signalling, contraction, and matrix degradation (GNG2, IGF1, ITGA2, LAMA1, LAMA4, COL6A3, ACTC1, MYL7, MMP24, and MMP16) were specifically enriched in stretched PM-SMCs, which may be relevant to their sensitivity to tension and ECM degradation. 38,39 Furthermore, we used LY294002, an inhibitor of PI3K/Akt signalling, for investigating the mechanism of tensile sensitivity in PM-SMCs and demonstrated that inhibition of PI3K/Akt signalling was able to reduce the sensitivity of PM-SMCs to stretching under low-strain stretching conditions.…”

Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression

“… 90 , 91 AKT can be also phosphorylated and activated by PDK2 at Ser473. 92 , 93 Activated AKT regulates cell proliferation, differentiation, migration, and apoptosis by activating or inhibiting downstream target proteins, such as Bad, 94 Caspase9, 95 NF-κB, 96 , 97 GSK-3, 98 FKHR, 99 , 100 p21, 101 p53 102 and FOXO1. 103 , 104 Aberrant activation of PI3K/AKT pathway has been found in a variety of cancers, 105 such as lung cancer, 106 esophageal cancer, 107 gastric cancer, 108 breast cancer, 109 laryngeal cancer, 110 gallbladder cancer, 111 and prostate cancer.…”