Abstract
AbstractVein graft disease is a chronic inflammatory disease and limits the late results of coronary revascularization. Calcitonin gene-related peptide (CGRP) inhibits macrophages infiltrated and inflammatory mediators, we hypothesized that transfected CGRP gene inhibits macrophages infiltrated and inflammatory mediators in vein graft disease. Autologous rabbit jugular vein grafts were incubated ex vivo in a solution of mosaic adeno-associated virus vectors containing CGRP gene (AAV2/1.CGRP) &x3001;escherichia coli lac Z gene (AAV2/1.LacZ) or saline and then interposed in the carotid artery. Intima/media ratio were evaluated at postoperative 4 weeks, Macrophages were marked with CD68 antibody by immunocytochemistry. Inflammatory mediators were mensurated with real-time PCR. Neointimal thickening was significantly suppressed in AAV2/1.CGRP group. Macrophages infiltrated and inflammatory mediators monocyte chemoattractant protein-1 (MCP-1)&x3001;tumor necrosis factor&x03B1;(TNF-&x03B1;)&x3001;inducible nitricoxide synthase (iNOS)&x3001;matrix metalloproteinase-9 (MMP-9) was significantly suppressed in AAV2/1.CGRP group.Gene transfected AAV2/1.CGRP suppressed neointimal hyperplasia in vein graft disease by suppressed macrophages infiltrated and inflammatory mediators.
Highlights
Autologous vein is usually using a material in artery rebuild,But, it was exposed to ischemia、trauma、inflammatory reaction and received high pressure and so on, embolism、spasm were appearred in early period, neointimal thickening and atherosclerosis were appearred in later,angioma occurred by chance,the phenomenon is vein graft disease.It is affected severely clinic effect of coronary artery bypass grafting (CABG)and peripheral vascular disease operation[1,2,3].Previous data shown that inflammatory cells infiltrated and inflammatory mediators released in the vein grafts, Macrophages and inflammatory mediators stimulated hyperplasia of vascular smooth muscle cells and neointimal thickening[4,5]
AAV vector,low immunogenicity of AAV may allow long-term transgene expression; Sen et al[16] showed that AAV1 have advantages over AAV2 for vascular gene delivery at low titres; Stachler et al[17] showed that mosaic AAV1 particles in a 50-100-fold enhancement in endothelial cell gene transfer and suggest that mosaic virions hold significant promise for targeted gene delivery to the vasculature.In the present study we showed that recombinant mosaic AAV2/1 facilitates an effective gene transfection in an autologous rabbit vein grafts model
Our data have shown that AAV2/1.Calcitonin gene-related peptide (CGRP) was transfected effectively to vein grafts(Fig. 1),AAV2/1 gene transfer of CGRP significantly reduced the ratio of intimal to medial area(Fig. 2) and dramatically reduced macrophage recruitment(Fig. 3) in vein grafts at 4 weeks after surgery.Our genic transfection means is a specific interest for the surgical perspective,Because the preparation and instillation of the viral solution can be performed in a bypass operation(Fig. 5)
Summary
Autologous vein is usually using a material in artery rebuild,But, it was exposed to ischemia、trauma、inflammatory reaction and received high pressure and so on , embolism、spasm were appearred in early period, neointimal thickening and atherosclerosis were appearred in later,angioma occurred by chance,the phenomenon is vein graft disease.It is affected severely clinic effect of coronary artery bypass grafting (CABG)and peripheral vascular disease operation[1,2,3].Previous data shown that inflammatory cells infiltrated and inflammatory mediators released in the vein grafts, Macrophages and inflammatory mediators stimulated hyperplasia of vascular smooth muscle cells and neointimal thickening[4,5]. Previous studies have shown that CGRP inhibits inflammatory cells and inflammatory mediators[8,9], protects endothelial function[10,11] and inhibits vascular smooth muscle cells hyperplasia[12,13].we sought to evaluate the effects of CGRP, using mosaic adeno-associated virus vectors gene transfer, on development of the vein graft disease in rabbits
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