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Identification of Stroke Biomarkers Using Proteomic Profiling of Extracellular Vesicles Derived from Human Blood: A Preliminary Study

ABSTRACT: Stroke is a devastating brain disease that causes extensive neurological impairment and high mortality. Rapid diagnosis and intervention of stroke are necessary to minimize neurological damage and improve recovery. Extracellular vesicles (EVs) have been identified as potential biomarkers for stroke, suggesting promising avenues for rapid diagnosis and prognostic assessments. This preliminary study aimed to evaluate the potential of EVs as biomarkers in the distinct pathophysiological mechanisms of hemorrhagic stroke (HS) and ischemic strokes (IS). We have identified proteins differentially expressed in EVs derived from the blood of HS and IS patients. EVs were isolated using an isolation kit, followed by proteomic analysis by LC-MS/MS to compare protein expression patterns. As a result of the proteomics analysis of blood-derived EVs, 15 proteins were upregulated and 4 downregulated in EVs from HS patients. Similarly, 14 proteins were upregulated and 5 downregulated in EVs from IS patients. Notably, 4 proteins were commonly upregulated and 1 protein was commonly downregulated across both conditions, with the remaining proteins uniquely altered in each type of stroke. To validate the proteomic findings, we confirmed the increased levels of CRP and PF4 in HS patients using ELISA, verifying their elevation in patient blood samples. These findings indicate that the proteins identified in blood-derived EVs hold the potential as biomarkers for HS, highlighting their utility for clinical application.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Cerebrovascular Disease

SUBMITTER: Kim Tae Yeon

LAB HEAD: Tae Yeon Kim

PROVIDER: PXD062958 | Pride | 2025-06-10

REPOSITORIES: Pride

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Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.

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Identification of Stroke Biomarkers Using Proteomic Profiling of Extracellular Vesicles Derived from Human Blood: A Preliminary Study

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