The Role Of MicroRNA-103/107in Vascular Remodeling Of Pulmonary Arterial Hypertension In Rats

Background:Pulmonary arterial hypertension (PAH) is a chronic respiratory disease characterised with persistent elevatory pulmonary arterial pressure because of congestion of pulmonary capillary. The pathogenesis of PAH has not been fully elucidated, and vascular remodeling induced by proliferation and migration of smooth muscle cells is thought as the main reason for PAH formation. It has been reported that some microRNAs were closely related with peripheral vascular remodeling. It has been documented that miR-103/107can inhibit cancer cell proliferation, angiogenesis and inflammation, either have other effects. Our preliminary experiments showed that expression of miR-103/107was down-regulated in pulmonary vascular tissue of pulmonary arterial hypertension rats, suggesting that miR-103/107might be involved in pulmonary vascular remodeling. The purpose of this study is to confirm the important role of miR-103/107in vascular remodeling of PAH, on this basis, investigating the relationship of miR-103/107and HIF-1β.Methods:The model of PAH was established in SD rats which were disposed under hypoxia (10%O2) for3weeks. The weight of right ventricle, the right ventricular systolic pressure and mean pulmonary artery pressure were determinated. The level of small pulmonary arterial remodeling was determinated by HE staining, the expression of HIF-1β protein was determinated by immunohistochemistry assay, Real Time PCR for the expression of miR-103/107and HIF-1β mRNA in pulmonary artery. In cultured rat pulmonary artery smooth muscle cells (PASMCs), cell proliferation was induced by hypoxia (3%O2), the expression of miR-103/107and HIF-1β mRNA were detected. In order to confirm the regulation effect of miR-103/107on the proliferation of PASMCs, exogenous miR-103/107mimic and miR-103/107inhibitor were used; and in order to confirm whether HIF-1β is the potential target of miR-103/107, the effects of miR-103/107mimic and miR-103/107 inhibitor on HIF-1β expression were observed.Results:In PAH rats induced by hypoxia, the mean pulmonary artery pressure and right ventricular systolic pressure were elevated, the right ventricle and pulmonary vascular were remolded, at the same time, the expression of miR-103/107was down-regulated concomitant with the increased expression of HIF-1β mRNA and HIF-1β protein in pulmonary artery. In isolated rat’s pulmonary artery smooth muscle cells, hypoxia caused cell proliferation accompany with a down-regulation of miR-103/107and a up-regulation of HIF-1β. When PASMCs were kept in the quiescent stage under normal oxygen and low serum (0.1%FBS), the expression of miR-103/107was up-regulated. Furthermore, the proliferation of PASMCs were inhibited by exogenous miR-103/107mimic, meanwhile, both the mRNA and protein of HIF-1β were inhibited by exogenous miR-103/107mimic, too. MiR-103/107inhibitor upregulated the mRNA and protein expression of HIF-1β.Conclusions:①iR-103/107is able to inhibit PASMCs proliferation and down-regulation of miR-103/107induced by hypoxia may contribute to vascular remodeling in PAH.②Down-regulation of HIF-1β by miR-103/107is involved in its inhibitory effect on PASMCs proliferation.