| Summary: | Background: Hypertension is a leading risk factor for cardiovascular disease (CVD) and premature death globally. Less than half of adults with hypertension are properly diagnosed and treated, highlighting a critical gap in current healthcare practices. The limitations of existing blood pressure measurement methods make it challenging to detect early cases of hypertension, which are often asymptomatic and, consequently, commonly undetected. This indicates the need for improved diagnostic and treatment strategies, particularly through precision medicine approaches. MicroRNAs (miRNAs) serve as master regulators of gene expression and are transported extracellularly by exosomes in various body fluids including plasma. Exosomal miRNAs have been implicated in hypertension development and have potential as non-invasive disease biomarkers. However, the profile of exosomal miRNA in a multi-ethnic population of essential hypertensives has yet to be elucidated.
Aim and objectives: This study aimed to investigate potential biomarkers of hypertension to enhance early detection. The objectives of this study were to screen and validate the differentially expressed exosomal miRNA profiles in essential hypertensive adults and identify their predicted targets and associated pathways.
Methods: Plasma exosomes were isolated and characterised. Total plasma exosomal RNA were extracted from ethnically Chinese and Malay stage 1 essential hypertensive and normotensive adults (30 to 55 years old). Samples were subjected to small RNA sequencing, differential expression analysis, target prediction, and pathway enrichment analysis. The differential expression profile was validated with real-time quantitative polymerase chain reaction (RTqPCR). The diagnostic value of the differentially expressed miRNAs were assessed. Enriched pathways and gene ontologies of predicted miRNA targets were compared against systemically dysregulated pathways to validate its biological function.
Results: Characterisation of plasma exosomes showed preferential release of medium- to large-vesicles with a significantly increased number of particles between 150 to 200 nm (P = 0.021) and an increased mean size (mean = 104.7 ± 19.3; P = 0.036) in hypertensives. Immunoblotting showed significantly xix reduced CD9 expression in hypertensives. The combination of hsa-miR-184, hsa-miR-432-5p, hsa-miR-1-3p, and hsa-miR-1246, along with BMI, efficiently identified hypertension risk with the highest area under the curve (AUC = 0.966, P < 0.0001) for the receiver’s operating characteristic (ROC) analysis. The miRNA signature together with systemically dysregulated pathways further highlighted the convergence of aberrant metabolic pathways in the development of hypertension.
Conclusions: This study provided the first comprehensive exosomal miRNAome in a multi-ethnic population of newly identified essential hypertensive adults. The differentially expressed miRNAs in essential hypertension provided leads for further validation and may provide unbiased insights into mechanisms involved in the early stages of hypertension, facilitating novel biomarker discovery or therapy development to alleviate the burden of CVDs.
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