Upregulation of miR-126-3p promotes human saphenous vein endothelial cell proliferation in vitro and prevents vein graft neointimal formation ex vivo and in vivo.

Qingxi Qu,Xin Zhao,Yanwen Bi,Yaqiu Guo,Qing Liu,Jie Xi,Weidong Bing,Xiangbin Meng,Xiao Bai

doi:10.18632/oncotarget.22365

Abstract

Poor long-term patency of vein grafts remains an obstacle in coronary artery bypass grafting (CABG) surgery using an autologous saphenous vein graft. Recent studies have revealed that miR-126-3p promotes vascular integrity and angiogenesis. We aimed to identify the role of miR-126-3p in the setting of vein graft disease and investigate the value of miR-126-3p agomir as a future gene therapy in vein graft failure. Expression analysis of circulating miR-126-3p in plasma from CABG patients established the basic clues that miR-126-3p participates in CABG. The in vitro results indicated that elevated miR-126-3p expression significantly improved proliferation and migration in human saphenous vein endothelial cells (HSVECs) by targeting sprouty-related protein-1 (SPRED-1) and phosphatidylinositol-3-kinase regulatory subunit 2 (PIK3R2), but not in human saphenous vein smooth muscle cells (HSVSMCs). Moreover, the therapeutic potential of miR-126-3p agomir was demonstrated in cultured human saphenous vein (HSV) ex vivo. Finally, local delivery of miR-126-3p agomir was confirmed to enhance reendothelialization and attenuate neointimal formation in a rat vein arterialization model. In conclusion, we provide evidence that upregulation of miR-126-3p by agomir possesses potential clinical value in the prevention and treatment of autologous vein graft restenosis in CABG.

Highlights

Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality according to a report from the World Health Organization
The benefits of coronary artery bypass grafting (CABG) surgery remain limited by the life expectancy of the saphenous vein graft, as over 50% of saphenous vein grafts will be occluded during the first decade after surgery, leading to recurrent symptoms, myocardial infarction or reoperative revascularization [5]
We found that circulating miR126-3p levels in patients undergoing CABG showed a brief rise during the perioperative period, which increased one day after surgery, peaked at 3 day after surgery, remained up-regulated at 7 days after surgery, and gradually declined to baseline at 14 days after surgery (Figure 1B, P < 0.05)

Summary

Introduction

Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality according to a report from the World Health Organization. The benefits of CABG surgery remain limited by the life expectancy of the saphenous vein graft, as over 50% of saphenous vein grafts will be occluded during the first decade after surgery, leading to recurrent symptoms, myocardial infarction or reoperative revascularization [5]. The principal process responsible for vein graft failure occurs as a result of massive neointimal hyperplasia, which takes place in response to vessel wall injury (distention, trauma) and hemodynamic changes, and is characterized by deposition of vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) components, such as proteoglycans and collagens [6]. Our previous study demonstrated that selective activation of reendothelialization after vein grafting attenuated www.impactjournals.com/oncotarget neointimal lesion formation [7].

Objectives

Methods

Results

Conclusion