Whole Genome Expression Profiling to Detect Novel Pathways in Restenosis of Peripheral Arteries

Abstract

Introduction: Despite progress in the development of vascular interventions, long-term patency after surgical treatment of atherosclerosis is still jeopardized by restenosis and occlusion of the reconstructed vessel segment. The mechanisms behind restenosis have been investigated mainly for the coronary vessels and can not be directly translated to the peripheral arterial bed. The aim of the study was to determine gene expression profiles associated with development of restenosis in the ilio-femoral arterial segment. Methods: Patients undergoing open surgery for occlusive ilio-femoral atherosclerosis were included in the study. Primary atherosclerotic plaques (n = 14) were compared with restenotic lesions (n = 7) using global gene expression analysis and morphological evaluation. Among the primary lesions two groups of patients were analyzed separately: those who developed restenosis within one year (n=5) and those who remained restenosis free (n=9). Even restenotic lesions from a synthetic prosthesis (n = 7) were included in the study. Differentially expressed genes were determined followed by enrichment analysis and functional characterization. Results: A total of 1626 genes were differentially expressed at least in one of the pairs of groups (P<0.01, fold change >1.2). About one third of differentially expressed genes encoded for noncoding RNAs (ncRNAs). Notably, a sizable proportion of genes, which were upregulated in the restenotic material were similar to those activated in the primary lesions prone to develop restenosis. In graft stenosis was characterized by a specific set of differentially expressed genes. Enrichment analysis demonstrated that cell survival, cell cycle progression and response to stress were predominant pathways associated with differentially expressed genes. Several transcription factors associated with early response to stress were upregulated in restenotic lesions compared to primary atherosclerotic plaques. In particular, subunits of the transcription factor AP1, factors of the nuclear receptor family (subfamily 4, group A), as well as their upstream regulators - members of EGR family of transcription factors were found overexpressed in secondary lesions. Conclusion: Major changes in gene expression profiles in restenotic ilio-femoral lesions were characterized by upregulation of transcription factors involved in cell cycle control and early response to stress. We could identify a certain gene expression profile of the primary atherosclerotic lesions prone to develop restenosis. The results of the study provide information about potential biomarkers and therapeutic targets for prevention of restenosis after vascular reconstructions.