Integrated miRNA/mRNA Counter-Expression Analysis Highlights Oxidative Stress-Related Genes CCR7 and FOXO1 as Blood Markers of Coronary Arterial Disease

Abstract

Our interest in the mechanisms of atherosclerosis progression (ATHp) has led to the recent identification of 13 miRNAs and 1285 mRNAs whose expression was altered during ATHp. Here, we deepen the functional relationship among these 13 miRNAs and genes associated to oxidative stress, a crucial step in the onset and progression of vascular disease. We first compiled a list of genes associated to the response to oxidative stress (Oxstress genes) by performing a reverse Gene Ontology analysis (rGO, from the GO terms to the genes) with the GO terms GO0006979, GO1902882, GO1902883 and GO1902884, which included a total of 417 unique Oxstress genes. Next, we identified 108 putative targets of the 13 miRNAs among these unique Oxstress genes, which were validated by an integrated miRNA/mRNA counter-expression analysis with the 1285 mRNAs that yielded 14 genes, Map2k1, Mapk1, Mapk9, Dapk1, Atp2a2, Gata4, Fos, Egfr, Foxo1, Ccr7, Vkorc1l1, Rnf7, Kcnh3, and Mgat3. GO enrichment analysis and a protein–protein-interaction network analysis (PPI) identified most of the validated Oxstress transcripts as components of signaling pathways, highlighting a role for MAP signaling in ATHp. Lastly, expression of these Oxstress transcripts was measured in PBMCs from patients suffering severe coronary artery disease, a serious consequence of ATHp. This allowed the identification of FOXO1 and CCR7 as blood markers downregulated in CAD. These results are discussed in the context of the interaction of the Oxstress transcripts with the ATHp-associated miRNAs.

FOXO1 and ANGPT2 relative gene expression in non-ST-segment elevation myocardial infarction among patients with or without type 2 diabetes

“…A recent study by Hueso et al [ 32 ] reported downregulation of FOXO1 gene expression in patients with stable CAD. Subjects in this study ( n = 10 with) were undergoing scheduled CABG surgery.…”

Differentially expressed mRNAs and their upstream miR-491-5p in patients with coronary atherosclerosis as well as the function of miR-491-5p in vascular smooth muscle cells

“…These miRNAs regulate the VSMC differentiation and coronary AS mainly through the modulation of target gene expression [ 3 , 25 , 26 ]. Previous studies have reported several miRNA-mRNA regulatory networks in AS [ 27 - 29 ]. For instance, upregulated miR-93 contributes to coronary AS pathogenesis through targeting ABCA1 [ 30 ].…”

Delicate Role of PD-L1/PD-1 Axis in Blood Vessel Inflammatory Diseases: Current Insight and Future Significance

“…Though terminal-exhausted CD8 + T cells express high levels of PD-1 during chronic infections, there is a possibility of re-invigorating the PD-1 high CD8 + T cells into an effector phase from a terminal differentiation state through FoxO1 that is accumulated in the nucleus [108]. Very recently, it was also shown that FoxO1 gene polymorphisms have been associated with the development of carotid atherosclerosis and were reported to be downregulated in coronary heart disease patients [186]. Not only this, FoxO1 might also function as a critical component for protecting PD-1 high CD8 + T cells from apoptosis, by increasing their survival through Bcl 2 upregulation.…”