Hypoxia is involved in hypoxic pulmonary hypertension through inhibiting the activation of FGF2 by miR-203

OBJECTIVE: The aim of this study was to investigate whether hypoxia in vivo can induce hypoxic pulmonary hypertension by inhibiting the activation of FGF2 by miR-203.

MATERIALS AND METHODS: We established a rat model of hypoxic pulmonary hypertension (HPH), and measured the right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (right ventricular hypertrophy index). The ventricular hypertrophy index (RVHI) was calculated and HE staining of the lung tissue of HPH rats was performed. We extracted pulmonary arterial smooth muscle cells (PASMCs) from rats and identified them by immunofluorescence assay. The expression of miR-203 in hypoxic PASMCs was detected by quantitative Real time-polymerase chain reaction (qRT-PCR). The proliferation and migration of PASMCs were detected by EDU (5-Ethynyl-2'-deoxyuridine), cell counting kit-8 (CCK-8) and scratch assay, respectively. Dual Luciferase reporting assay and Western blot were used to detect the binding of miR-203 and FGF2.

RESULTS: The results of qRT-PCR showed that miR-203 expression in rat PASMCs was significantly lower than that in normoxia control group at 24 h and 48 h after hypoxic treatment. EDU, CCK8 and scratch test results showed that proliferation and migration ability of PASMCs were weakened after overexpression of miR-203, and vice versa. Dual Luciferase reporter gene assays and Western blot experiments showed that miR-203 could target and combine with FGF2 to inhibit its expression. In vivo experiments showed that low expression of FGF2 could lead to decreased RVSP and RVHI, decreased FGF2 protein levels, and decreased WT% and (PM+FM)% in hypoxia-treated rats.

CONCLUSIONS: Hypoxia in vivo is involved in the development of HPH by inhibiting the activation of FGF2 by miR-203. Meanwhile, specific inhibition of FGF2 can reduce hypoxia-induced pulmonary hypertension and improve pulmonary vascular remodeling.

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