Drug-interacting gene expression levels differ between atherosclerotic plaque subtypes

Abstract

Abstract Background Recent transcriptomic-based clustering of human atherosclerotic plaques revealed that plaques have a diversity and complexity that cannot be accurately described by classical concepts. Previous plaque RNA sequencing that we performed identified five major plaque types that reflect the severity of the atherosclerotic disease. These include the following plaque subtypes: 0. Fibro-collagenous, 1. Intermediate, 2. Lipo-necrotic, 3. Fibro-inflammatory, and 4. Fibro-cellular. We hypothesised that identifying these different plaque types could explain differential responses following drug treatment. Objective To assess differential expression levels of drug-responsive genes between the earlier described five plaque subtypes. For this pilot experiment, we selected genes that are differentially expressed after colchicine treatment in smooth muscle cells and endothelial cells. Methods A web-based search identified 46 published colchicine interacting genes. Colchicine was also applied to smooth muscle and endothelial cells to identify direct-effect genes via differential gene expression analysis. Differences in gene expression between plaque types were assessed for those genes that were considered drug-responsive. Finally, to model the effect of colchicine on an atherosclerotic plaque, we projected the in vitro derived expression changes onto the gene expression data from carotid plaques of 654 patients that participated in the ATHERO-EXPRESS study. Results 34 out of the 46 publicly known colchicine interacting genes were differently expressed between plaque types (Figure 1). These genes included established determinants of cell motility and atherosclerosis development (SCD, ITGB1, Tubulins). Furthermore, in-silico colchicine treatment revealed colchicine's strong effect on the atherosclerotic plaques' transcriptome. We are currently assessing if these perturbations may lead to changes in plaque subtypes. Conclusion The pilot data demonstrated major differences in drug-interacting gene expression levels in advanced atherosclerotic lesions. Therefore, novel and standard drugs used to treat atherosclerosis may have varying effects depending on the atherosclerotic plaque subtype.Figure 1