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

The aim of the present study was to investigate the role of microRNA15a5p (miR15a5p) in pulmonary arterial hypertension (PAH) and elucidate the underlying proapoptotic mechanism. Reverse transcriptionquantitative PCR analysis and gene microarray hybridization were used to measure the expression of miR15a5p in the lung tissues of rats with monocrotaline (MCT)induced PAH. Flow cytometry and caspase3/9 activity assays were adopted to measure the apoptosis of pulmonary artery smooth muscle cells (PASMCs). The expression of apoptosisrelated proteins was analyzed using western blotting. The results demonstrated that the expression of miR15a5p was significantly increased in the lung tissues of rats with MCTinduced PAH. In addition, the overexpression of miR15a5p reduced PASMC proliferation, induced apoptosis, promoted the activity of caspase3/9, induced the protein expression of Bcell lymphoma 2associated X protein (Bax), decreased the expression of Bcell lymphoma 2 (Bcl2), increased inflammation, as indicated by the expression of tumor necrosis factoralpha (TNF)alpha and interleukin (IL)1beta, IL6 and IL18, suppressed the protein expression of vascular endothelial growth factor (VEGF), and promoted the protein expression levels of phosphorylated (p)p38 mitogenactivated protein kinase (p38) and matrix metalloproteinase (MMP)2 in the PASMCs of rats with MCTinduced PAH. By contrast, the downregulation of miR15a5p increased cell proliferation, decreased apoptosis, reduced the activity of caspase3/9 and the protein expression of Bax, increased the expression of Bcl2, inhibited inflammation (as suggested by the expression of TNFalpha, IL1beta, IL6 and IL18), induced the protein expression of VEGF, and suppressed the protein expression of pp38 and MMP2 in the PASMCs of rats with MCTinduced PAH. The inhibition of VEGF attenuated the effects of the overexpression of miR15a5p on the inhibition of cell proliferation, apoptotic rate, caspase3/9 activity and protein expression of Bax, and it attenuated the increased inflammation, as indicated by the protein expression of p38 and MMP2 in the PASMCs. In conclusion, the data of the present study demonstrated that miR15a5p induced the apoptosis of PASMCs in an animal model of PAH via the VEGF/p38/MMP2 signaling pathway. However, further research is required to fully elucidate the role of miR15a5p in the development of PAH.