Abstract
BackgroundTranscriptional profiles are available for a variety of cardiovascular-related diseases. The goal of this study was to compare blood transcriptional profiles of the Toll-like receptor (TLR), T-cell receptor (TCR), and B-cell receptor (BCR) signaling pathways in asymptomatic atherosclerosis, acute ischemic stroke, and myocardial infarction patients to identify common mechanisms of immune regulation and their association with epigenetic regulation.Methods and resultsPeripheral blood gene expression profiles from human atherosclerosis-related diseases and healthy controls were downloaded from Gene Expression Omnibus (GEO). Genes in the TLR, TCR, and BCR pathways were retrieved from the NCBI BioSystems database. Significance of gene enrichment and concordance of expression changes in each pathway was compared between studies. Gene expression was significantly correlated across the three disease conditions (p<10−15) and the proportion of significant genes was high (30~60%, p<0.001). Hub genes identified by weighted gene co-expression network analysis (WGCNA) in the TCR/BCR sub-network, including CD81 and TCR-CD3ζ, were significantly down-regulated and highly correlated with DNA (cytosine-5-)-methyltransferase 1 (DNMT1).ConclusionCommon biologically relevant networks associated with immune regulation in stroke, atherosclerosis, and myocardial infarction were discovered. Given the high correlation of DNMT1 with these immune signaling pathways, epigenetic regulation may contribute to the coordination of innate and adaptive immune response in all CVD disease states. Down-regulation of the TCR-BCR axis in the adaptive immune system offers critical information for the investigation of the functional mechanisms underlying chronic inflammation-induced immune suppression in cardiovascular disease and stroke.
Highlights
Atherosclerosis is one of the most common causes of death and disability in the United States [1]
Common biologically relevant networks associated with immune regulation in stroke, atherosclerosis, and myocardial infarction were discovered
DNA (cytosine-5-)-methyltransferase 1 (DNMT1) with these immune signaling pathways, epigenetic regulation may contribute to the coordination of innate and adaptive immune response in all CVD disease states
Summary
Atherosclerosis is one of the most common causes of death and disability in the United States [1]. Previous studies using gene expression profiling indicate that increased expression of genes involved in the toll-like receptor (TLR) signaling pathway are common in patients with asymptomatic atherosclerotic cardiovascular disease [4] and acute IS [5]. It is likely that epigenetic modification may play a key role in coordinating the innate and adaptive immune response Despite these novel discoveries, the interplay between DNA methylation and immune signaling pathways in atherosclerotic diseases has largely been unexplored outside the controlled laboratory setting. The goal of this study was to compare blood transcriptional profiles of the Toll-like receptor (TLR), T-cell receptor (TCR), and B-cell receptor (BCR) signaling pathways in asymptomatic atherosclerosis, acute ischemic stroke, and myocardial infarction patients to identify common mechanisms of immune regulation and their association with epigenetic regulation
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