Abstract
Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia, related in part to implantation injury. The cell-specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells (EC) and medial smooth muscle cells (SMC) from canine vein grafts, 2 hours (H) to 30 days (D) following surgery. Our results demonstrate a robust genomic response beginning at 2 H, peaking at 12–24 H, declining by 7 D, and resolving by 30 D. Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses, apoptosis, mitosis, and extracellular matrix reorganization in both cell types. Through backpropagation an integrated network was built, starting with genes differentially expressed at 30 D, followed by adding upstream interactive genes from each prior time-point. This identified significant enrichment of IL-6, IL-8, NF-κB, dendritic cell maturation, glucocorticoid receptor, and Triggering Receptor Expressed on Myeloid Cells (TREM-1) signaling, as well as PPARα activation pathways in graft EC and SMC. Interactive network-based analyses identified IL-6, IL-8, IL-1α, and Insulin Receptor (INSR) as focus hub genes within these pathways. Real-time PCR was used for the validation of two of these genes: IL-6 and IL-8, in addition to Collagen 11A1 (COL11A1), a cornerstone of the backpropagation. In conclusion, these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury, and identifying novel targets for its prevention.
Highlights
Surgical bypass grafting using autologous vein conduits is the cornerstone therapy for coronary and peripheral arterial occlusive disease
Purity of endothelial cells (EC) and smooth muscle cells (SMC) isolated by LCM Purity of EC and medial SMC retrieved by laser capture microdissection (LCM) from control veins and vein grafts was determined by Q-RT-PCR using the cell-specific markers, Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1/CD31) for EC and Myosin Heavy Chain II (MHCII) for SMC
MHCII expression was lower in control EC as compared to control SMC, and in graft EC as compared to graft SMC at all timepoints, suggesting that there was negligible contamination of EC with SMC (Figure S1B)
Summary
Surgical bypass grafting using autologous vein conduits is the cornerstone therapy for coronary and peripheral arterial occlusive disease. About 250,000 coronary artery bypass grafts (CABG) and about 80,000 lower extremity vein graft implantations are performed each year with an average cost of 44 billion dollars [1,2,3]. More than 50% of CABG fail within 10 years, and 30–50% of lower extremity vein grafts fail within 5 years from surgery [4]. Mid-term failure due to intimal hyperplasia (IH) causing stenosis and occlusion is by far the most common cause (.70%) of vein graft failure [6]. These numbers beg better understanding of the molecular basis of these lesions, in order to define targeted therapies that would reduce failure rate
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