M. J. Zhu1, 2, 3, N. Momi1, 3, M. K. Bhasin4, F. W. LoGerfo1, 3, L. Pradhan-Nabzdyk1, 3 1Beth Israel Deaconess Medical Center, Vascular Surgery, Boston, MA, USA 2Boston University, School Of Medicine, Boston, MA, USA 3Harvard School Of Medicine, Brookline, MA, USA 4Emory University School Of Medicine, Atlanta, GA, USA
Introduction:
Intimal hyperplasia (IH) in response to vascular injury has remained a common problem, such as in vein graft surgery. In recent years, few genomic studies have shed light on the transcriptomic mechanisms of IH or potential genetic targets for therapy. Here, we compared transcriptomic profiles from three studies on vascular injury using a systems biology approach to identify genetic targets for prevention and treatment of IH.
Methods:
We included two temporal microarray studies on canines: one on whole vein graft tissue (study1-PMID: 14981462) and the other on endothelial cells (ECs) and smooth muscle cells (SMCs) harvested from vein graft (study2-PMID: 22720046), both following bypass surgery. A third study was included on aortic ECs exposed to wall sheer stress (study3-GSE29376). Datasets were Robust Multichip Average normalized, and genes with significant transcriptomic activity were identified using the following analysis
Methods: Differentially Expressed Gene (DEG) analysis (p<0.05 and log2 fold change [lfc]=1), Gene Set Enrichment Analysis (GSEA, p<0.05 and FDR <0.3), WGCNA-based correlation analysis (z score <2), Cytoscape-based interactive network analysis, and Ingenuity Pathway Analysis (IPA). Genes identified by IPA were analyzed for changes in gene expression between experimental (exposed to vascular injury) versus control (no vascular injury) conditions using t-tests, and genes with significant changes in transcriptomic activity in response to injury across multiple studies were identified. Analyses were performed sequentially (Fig 1).
Results:
The sequential analyses identified 113 dysregulated genes between experimental and control samples in one or more of the three studies. These genes are implicated in immune response, extracellular matrix remodeling, cell migration, cell proliferation, and cell differentiation. Only 9 genes demonstrated consistent upregulation or downregulation in gene expression across the three different studies.
Conclusion:
Systems biology analytic approach to the three studies of vascular injury has identified 9 signature genes that show consistent upregulation (SNAI2, PTTG1, CCNA2, CCNB1, CIT, JUNB, and HAT1) or downregulation (CAV1 and VEGFB) across all studies. These genes may serve as potential targets for future therapeutics to diminish intimal hyperplasia.
