MicroRNA410 Inhibits Pulmonary Vascular Remodeling via Regulation of Nicotinamide Phosphoribosyltransferase

Hui Gao,Yangbasai Dong,Jiwang Chen,Yifang Wang,Shuangping Zhao,Roberto F Machado,Tianji Chen,Yang Song

doi:10.1038/s41598-019-46352-z

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) upregulation in human pulmonary artery endothelial cells (hPAECs) is associated with pulmonary arterial hypertension (PAH) progression and pulmonary vascular remodeling. The underlying mechanisms regulating NAMPT expression are still not clear. In this study, we aimed to study the regulation of NAMPT expression by microRNA410 (miR410) in hPAECs and explore the role of miR410 in the pathogenesis of experimental pulmonary hypertension. We show that miR410 targets the 3′ UTR of NAMPT and that, concomitant with NAMPT upregulation, miR410 is downregulated in lungs of mice exposed to hypoxia-induced pulmonary hypertension (HPH). Our results also demonstrate that miR410 directly inhibits NAMPT expression. Overexpression of miR410 in hPAECs inhibits basal and VEGF-induced proliferation, migration and promotes apoptosis of hPAECs, while miR410 inhibition via antagomirs has the opposite effect. Finally, administration of miR410 mimics in vivo attenuated induction of NAMPT in PAECs and prevented the development of HPH in mice. Our results highlight the role of miR410 in the regulation of NAMPT expression in hPAECs and show that miR410 plays a potential role in PAH pathobiology by targeting a modulator of pulmonary vascular remodeling.

Highlights

As a new class of posttranscriptional regulators of many cardiac and vascular diseases[10], microRNAs are a group of endogenous, small non-coding RNAs which regulate gene expression[11]
To determine the interaction of miR410 with the Nicotinamide phosphoribosyltransferase (NAMPT) 3′-UTR, we overexpressed or inhibited miR410 expression using human miR410 mimics or inhibitors, respectively, in human pulmonary artery endothelial cells (hPAECs) co-transfected with a sequence-verified clone of NAMPT-3′UTR reporter vector designed for microRNA target validation
This work expands and complements our previous study[9], where we found that NAMPT was upregulated in the plasma, lungs, and PAECs isolated from patients with pulmonary arterial hypertension (PAH) and in PAECs from different rodent models of PH

Summary

Introduction

As a new class of posttranscriptional regulators of many cardiac and vascular diseases[10], microRNAs (miRs) are a group of endogenous, small (approximately 22 nucleotides) non-coding RNAs which regulate gene expression[11]. Several studies have identified miRs associated with PAH and with experimental models of pulmonary hypertension[12,13,14]. They may be involved in the control of almost all physiological and pathological cellular processes, including several pathways relevant to pulmonary vascular remodeling. Regulate NAMPT expression and could, in turn, affect proliferation, migration and apoptosis of PAECs. regulate NAMPT expression and could, in turn, affect proliferation, migration and apoptosis of PAECs These specific miRs may be therapeutic targets for PAH

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