Abstract 222: SCARA5 and Suprabasin are Hub Genes of Co-expression Network Modules Associated with Peripheral Vein Graft Patency
Introduction: About 30% of vein grafts fail because of intimal hyperplasia or negative remodeling. We have reported that vein graft cells from patients that develop stenosis proliferate more than cells from patients that maintain patent grafts. We have now analyzed gene expression of the same cell lines using a systems biology approach to cluster genes into modules based on their co-expression patterns and to correlate the results with graft outcome, growth data from our prior study, and with new studies of migration and matrix remodeling.
Methods: RNA from 4 hour serum- or PDGF-BB-stimulated cells (13 non-stenotic and 7 stenotic cell lines) was used for microarray analysis of gene expression followed by weighted gene co-expression network analysis. Cell migration in microchemotaxis chambers in response to PDGF-BB and cell-mediated collagen gel contraction in response to serum were also determined. Gene function in growth or collagen gel contraction was determined using siRNA to inhibit gene expression.
Results: Neither migration nor collagen gel contraction were correlated with graft outcome. While 1,188 and 1,340 genes were differentially expressed in response to serum and PDGF, respectively, graft outcome was not correlated with expression of any single gene. Network analysis revealed one module each from the separate analysis of the PDGF and serum data sets, which were called “Yellow” and “Skyblue” respectively, that were correlated with later graft stenosis (P=.005 and .02, respectively). Yellow was also associated with increased cell growth, and Skyblue was also associated with inhibition of collagen gel contraction. The hub genes for Yellow and Skyblue (i.e. the gene most correlated with other genes in the module), SCARA5 and SBSN, respectively, were tested for effects on proliferation and collagen contraction. SCARA5, but not SBSN, inhibited proliferation, and SBSN, but not SCARA5, inhibited collagen gel contraction.
Conclusion: Using weighted gene co-expression network analysis of cultured vein graft cell gene expression, we have discovered a small number of genes of interest in vein graft failure. Further experiments are needed to discriminate the roles these genes play in vein graft healing starting with the module hub genes SCARA5 and SBSN.
Author Disclosures: R.D. Kenagy: Research Grant; Significant; HL30946. M. Civelek: Research Grant; Significant; HL121172. S. Kikuchi: None. L. Chen: Research Grant; Significant; HL30946. A. Grieff: None. M. Sobel: Research Grant; Significant; HL30946. A.J. Lusis: Research Grant; Significant; HL30568. A.W. Clowes: Research Grant; Significant; HL30946.
- © 2015 by American Heart Association, Inc.