Inhibition of miR-495 Improves Both Vascular Remodeling and Angiogenesis in Pulmonary Hypertension

Abstract

Background and Aims: Pulmonary hypertension (PH) is a chronic progressing vascular disease characterized by pulmonary arteriole remodeling and loss of pulmonary microvasculature. The aim of this study was to investigate a potential role for the miR-495 in PH pathogenesis and to explore its therapeutic potential in PH. Methods: Male C57BL/6J mice were injected with SU5416 weekly during 3 weeks of exposure to 10% oxygen to cause PH. We first tested the effects of adeno-associated virus 9 (AAV9) delivery which was specifically designed to block miR-495 in the lungs of the PH model. Then, the biological function of miR-495 was analyzed in cultured pulmonary arterial endothelial cells (PAECs) under hypoxic condition. Results: The inhibition of miR-495 improves hemodynamics and vascular remodeling in PH. At the same time, these effects were associated with increases in angiogenic transcription factor VEZF1 and marked upregulation of other angiogenic genes such as Angpt-1 and IGF1. In vitro, cultured mouse PAECs were transfected with miR-495 inhibitor or miR-495 mimics. Both the flow cytometry results and CCK8 assay showed that miR-495 inhibitor increased the percentage of cells in the G2/M+S phase, and the wound healing assays indicated that the migration capacity of PAECs transfected with miR-495 inhibitor was increased compared to the inhibitor-NC cells. Conclusions: Our results indicate that AAV9-TuD-miR-495 delivery improves hemodynamic and pulmonary vascular structural changes in PH mice.

Adhesion of monocytes and endothelial cells isolated from the human aorta suppresses by miRNA-PEI particles

“…According to several studies, miR-495 reduces inflammatory events by inhibiting the inflammasome signaling pathway [ 53 ] and may act as a tumor suppressor by directly targeting PIK3R1 gene in endometrial cancer cells [ 54 ]. Moreover, the inhibition of miR-495 improved pulmonary vascular structural changes in mice [ 55 ]. The miR-495 also induced potent cardiomyocyte proliferation due to suppression of coactivator Cited 2 factor [ 56 ].…”

Non-coding RNAs function as diagnostic biomarkers and therapeutic targets in pulmonary arterial hypertension

“…Inhibition of miR-495 via adeno-associated virus type 9 (AAV9) effectively mitigates hemodynamic abnormalities and structural changes in the pulmonary vasculature in the mouse model of PAH, thereby improving vascular remodeling and angiogenesis. This represents a novel potential therapeutic approach for human pulmonary hypertension [45].…”

Therapeutic aspect of microRNA inhibition in various types of hypertension and hypertensive complications

“…In addition, Fu et al (2019) performed an experiment both in vivo and in vitro using male C57BL/6J mice and pulmonary arterial endothelial cells (PAECs) respectively. To induce PH, male C57BL/6J mice were injected with SU5416 once a week for three weeks while exposed to 10% oxygen.…”