The Role And Mechanism Of MicroRNA-146a Sponge In Restenosis After Vein Grafting

Background:The saphenous vein is the most widely used vascular graft material in coronary artery bypass grafting(CABG).However,studies have shown that 20%-50% of patients with CABG have saphenous vein restenosis within 5 years after operation.The rate of restenosis of the bridge vein was more than 50% after 10 years.How to effectively prevent and treat restenosis after CABG is a difficult problem in the field of cardiovascular surgery.miR-146 a is an important factor regulating the proliferation of vascular smooth muscle cells(VSMC).In addition,studies have shown that miR-146 a is involved in the regulation of intimal hyperplasia after vascular balloon injury.Objective: This study aims to investigate whether miR-146 a participates in the development of intimal hyperplasia in rat vein grafts by constructing a rat vein graft model.In addition,miRNA Sponge technology is used to construct miR-146a-Sponge and verify whether it can Effectively inhibit the intimal hyperplasia in the vein grafts after surgery.Methods: An animal model of rat vein grafting was established,and the expression of miR-146 a in the vein grafts at different time points after surgery was detected by qRT-PCR.The miR-146 a silencing adenovirus expression vector was constructed by miRNA Sponge technology and transfected into VSMC.The effect of miR-146a-Sponge on the proliferation of VSMC was detected by cell counting,CCK-8 and BrdU assay.A wound healing(scratch)assay was used to detect miR-146aSponge’s impact on VSMC migration.The grafted vein was locally transfected with 20% poloxamer F-127-0.25% trypsin-miR-146a-Sponge hybrid gel to detect the effect of miR-146a-Sponge on intimal hyperplasia of vein grafts.Results: The expression of miR-146 a in the vein grafts was significantly increased in different time groups after vein grafting.miR-146a-Sponge significantly inhibited the proliferation and migration of VSMC.Animal experiments further indicated that miR-146a-Sponge can effectively inhibit the neointimal formation in rat vein grafts.Mechanistically,we identified the Krüppel-like factor 4(KLF4)as a potential downstream target gene of miR-146 a in vein grafts.Conclusion: Our data show that miR-146 a sponge gene therapy could effectively reduce miR-146 a activity and attenuate neointimal formation in vein grafts,suggesting its potential therapeutic application for prevention of vein graft failure.