Abstract 18255: MicroRNA Analysis in Experimental Models of Vein Graft Neointima Formation Indentifies a Critical Role For Mir-21 in Neointima Formation
Background: Coronary artery bypass grafting (CABG) is an established treatment to relieve the symptoms of ischemic heart disease. However premature graft failure, in saphenous veins is a major limitation. One of the principal etiological factors responsible for vein graft failure is activation and phenotypic modulation of smooth muscle cells (SMC), resulting in accelerated rates of proliferation and migration. MicroRNAs (miRNAs) are short, single stranded, non-coding RNAs that play important roles in modulating cell phenotypes through regulation of gene expression.
Methods and results: In order to assess the expression levels of miR-21 in the progression of vein graft neointimal formation we quantified miR-21 levels in three well-established models of vein graft disease. These were the in vivo porcine model of interposition graft, the isogenic mouse model, as well as the ex vivo human sapehnous vein model of neointimal formation. MiR-21 levels were up-regulated approximately 7-fold in both the porcine and murine models at 7 and 28 days following grafting (n=6). In surgically prepared HSV which were subjected to culture ex vivo we found that miR-21 levels were elevated approximately 3-fold following 7 and 14 days of culture (n=6). In situ localization in the HSV demonstrated that miR-21 was expressed most intensely in the neointimal layer of HSV which also stained positive for SMC actin. Co-localization studies in murine vein grafts revealed that miR-21 was localised to areas of the graft that stained positive for proliferating cell nuclear antigen with substantial co-staining with SMC actin. We assessed the potential functional role of miR-21 in vein graft failure using miR-21 knockout mice. Analysis of neointimal lesion size in miR-21 knockout mice revealed an 81% reduction in neointimal area compared to wild type controls (p< 0.0001, n=7-10/group).
Conclusion: These findings demonstrate that miR-21 is up-regulated in multiple models of vein graft disease and that genetic abolition of miR-21 levels can attenuate neointimal formation in response to grafting. Therein, modulation of miR-21 expression represents a novel therapeutic opportunity in the setting of vein graft neoinitma formation.
- © 2012 by American Heart Association, Inc.