MicroRNA‑15a‑5p induces pulmonary artery smooth muscle cell apoptosis in a pulmonary arterial hypertension model via the VEGF/p38/MMP‑2 signaling pathway

Abstract

The aim of the present study was to investigate the role of microRNA-15a-5p (miR-15a-5p) in pulmonary arterial hypertension (PAH) and elucidate the underlying pro-apoptotic mechanism. Reverse transcription-quantitative PcR analysis and gene microarray hybridization were used to measure the expression of miR-15a-5p in the lung tissues of rats with monocrotaline (McT)-induced PAH. Flow cytometry and caspase-3/9 activity assays were adopted to measure the apoptosis of pulmonary artery smooth muscle cells (PASMcs). The expression of apoptosis-related proteins was analyzed using western blotting. The results demonstrated that the expression of miR-15a-5p was significantly increased in the lung tissues of rats with McT-induced PAH. In addition, the overexpression of miR-15a-5p reduced PASMc proliferation, induced apoptosis, promoted the activity of caspase-3/9, induced the protein expression of B-cell lymphoma 2-associated X protein (Bax), decreased the expression of B-cell lymphoma 2 (Bcl-2), increased inflammation, as indicated by the expression of tumor necrosis factor-α (TNF)-α and interleukin (IL)-1β, IL-6 and IL-18, suppressed the protein expression of vascular endothelial growth factor (VEGF), and promoted the protein expression levels of phosphorylated (p)-p38 mitogen-activated protein kinase (p38) and matrix metalloproteinase (MMP)-2 in the PASMcs of rats with McT-induced PAH. By contrast, the downregulation of miR-15a-5p increased cell proliferation, decreased apoptosis, reduced the activity of caspase-3/9 and the protein expression of Bax, increased the expression of Bcl-2, inhibited inflammation (as suggested by the expression of TNF-α, IL-1β, IL-6 and IL-18), induced the protein expression of VEGF, and suppressed the protein expression of p-p38 and MMP-2 in the PASMcs of rats with McT-induced PAH. The inhibition of VEGF attenuated the effects of the overexpression of miR-15a-5p on the inhibition of cell proliferation, apoptotic rate, caspase-3/9 activity and protein expression of Bax, and it attenuated the increased inflammation, as indicated by the protein expression of p38 and MMP-2 in the PASMcs. In conclusion, the data of the present study demonstrated that miR-15a-5p induced the apoptosis of PASMcs in an animal model of PAH via the VEGF/p38/MMP-2 signaling pathway. However, further research is required to fully elucidate the role of miR-15a-5p in the development of PAH.

Circular RNA circFADS2 is Overexpressed in Sepsis and Suppresses LPS-Induced Lung Cell Apoptosis by Inhibiting the Maturation of miR-15a-5p

“…MiR-15a-5p induces the apoptosis of pulmonary artery smooth muscle cells by interacting with VEGF/p38/MMP-2 signaling pathway [15]. In this study, we showed that miR-15a-5p was downregulated in sepsis and the downregulation is likely induced by LPS.…”

“…CircRNA circFADS2 in a recent study was proven to play protective role in LPS-induced cell apoptosis, which contributes to sepsis [14]. Our preliminary RNA-seq analysis revealed the altered the expression of circFADS2 as well as inverse correlation with miR-15a-5p, which may promote pulmonary diseases [15]. This study was therefore performed to explore the role circFADS2 in sepsis and its interaction with miR-15a-5p, with a focus on sepsis-induced lung injury.…”

The Function of microRNAs in Pulmonary Embolism: Review and Research Outlook

“…Therefore, specific miRNAs that are capable of modulating MMP expression also have potential treatment or prediction value in PE pathogenesis. Zhang et al elucidated that miR-15a-5p expression was significantly increased in the lung tissue of PAH rats and that artificial overexpression of miR-15a-5p led to increased expression of MMP-2 ( Zhang et al, 2020b ). Some studies found that inhibition or degradation of the corresponding mRNA of MMP-12 could be a solution to treat pathological lung tissue remodeling ( Garbacki et al, 2009 ).…”

Circular RNA circFADS2 is overexpressed in sepsis and suppresses LPS-induced lung cell apoptosis by inhibiting the maturation of miR-15a-5p

“…MiR-15a-5p induces the apoptosis of pulmonary artery smooth muscle cells by interacting with VEGF/p38/MMP-2 signaling pathway [ 14 ]. In this study, we showed that miR-15a-5p was downregulated in sepsis, and the downregulation is likely induced by LPS.…”

“…CircRNA circFADS2 is proven to play a protective role in LPS-induced cell apoptosis, contributing to sepsis [ 13 ]. Our preliminary RNA-seq analysis revealed that the altered circFADS2 expression in sepsis is inversely correlated with miR-15a-5p, which may promote pulmonary diseases [ 14 ]. Therefore, this study was performed to explore the role of circFADS2 in sepsis and its interaction with miR-15a-5p, with a focus on sepsis-induced lung injury.…”