Abstract 20279: A Bioinformatics Approach Reveals Mechanism of Pericardial Fluid Exosome Action in Promoting Ischemia in Diabetic Patients

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Type 2 diabetes mellitus (T2DM) impairs endogenous reparative angiogenic processes thus leading to ischaemic heart disease (IHD). Recently, it has come to light that extracellular vesicles (EVs) e.g exosomes that are released by different types of cells and accumulate in biological fluids are powerful tools of cell-to-cell communication with high relevance in cardiovascular homeostatic and pathogenic processes. The characterization of exosomes in human biological fluids is still largely under-studied. Our group has shown that the pericardial fluid (PF) exosomes promote survival and angiogenesis both in vivo and in vitro. We hypothesize that in healthy individuals, PF exosomes promote reparative actions on vascular cells whereas this is disturbed by T2DM. To investigate this, we take on a bioinformatics approach to elucidate the putative mechanisms of pericardial fluid (PF) exosome action in promoting IHD in diabetes. We have performed a high-throughput proteomic screening of exosomes extracted from PF of IHD patients with or without diabetes and non-IHD, non-diabetic patients undergoing mitral valve repair (MVR) surgery (controls). In parallel, we performed miRNA profiling of PF exosomes from the same patient categories. Using R package Limma, we have identified proteins that are highly expressed under T2DM. The top candidates include APAF-1 (apoptotic peptidase activating factor-1), a cytoplasmic protein that initiates apoptosis. Using hierarchical clustering and gene set enrichment analysis (GSEA); we identified groups of miRs that are differentially expressed (DE) under T2DM. Employing a network approach, we integrated miR and protein data by predicting targets of groups of DE miRs and connected them to DE proteins. An interesting group containing hsa-let-7b-5p corresponds to the pathway: Angiogenesis. Let-7b-5p has been previously identified as a mediator of the positive actions of PF exosomes in absence of IHD and diabetes. Our analysis shows that this group is depleted in T2DM and predicted to target APAF-1 thus pointing towards the pro-apoptotic and anti-angiogenic effect of T2DM exosomes. To conclude, this bioinformatics analysis gives aninsight into some of the mechanisms of PF exosome action in promoting IHD in T2DM patients.

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