A Multiomics Approach to Defining Target‐Organ Injury in Youths With Primary Hypertension: The SHIP AHOY Cohort

Background Primary hypertension in childhood tracks into adulthood and is associated with increased cardiovascular risk. Studies conducted in individuals aged <18 years, an age group without many of the confounding comorbid cardiovascular disease risk factors in adults, provide an opportunity to explore early cardiovascular target‐organ injury. Methods Youths (n=132, mean age, 15.8 years) were stratified by blood pressure (BP) as low–BP, mid‐BP, and high–BP and by left ventricular mass index as low‐and high left ventricular mass index. Systemic circulating RNA, microRNA, and methylation profiles in peripheral blood mononuclear cells and deep proteome profiles in serum were determined using high‐throughput sequencing techniques. In vitro cell culture experiments assessed angiotensin II‐ and microRNA‐mediated Vash1 (vasohibin‐1 protein) regulation and Vash1‐mediated hypertrophic response. Results In high‐BP youths, transcriptomics analysis identified 7 differentially expressed genes, including elevated VASH1 transcripts but correspondingly diminished levels of its microRNA (microRNA‐24‐3p and microRNA‐335‐5p). In vitro experiments revealed that either angiotensin II treatment, microRNA‐24‐3p or microRNA‐335‐5p overexpression, reduced endogenous VASH1 transcript levels. In contrast, exogenous Vash1 protein treatment induced cellular hypertrophy. Hypermethylation of GSE1 , POTE1 , and MN1 ; hypomethylation of MAD1L1 and SH3BP4 ; elevated Protein Z and diminished Superoxide dismutase 3 protein levels were observed in mid‐BP and high‐BP+high–left ventricular mass index groups. In youths with high–BP and high–left ventricular mass index, HYAL1 transcripts and Hyaluronidase 1 protein were elevated, suggesting the significant involvement of extracellular matrix in cardiovascular target‐organ injury. Conclusions The integration of multiomics data in this unique pediatric population during the early phase of high BP provides evidence of molecular changes that reveal both potential drug targets and strategies for ameliorating BP‐mediated cardiovascular target‐organ injury.