Kuffel, G. | bioRxiv Science

bioRxiv2024

A Multi-Omics Approach to Defining Target Organ Injury in Youth with Primary Hypertension

BACKGROUNDPrimary hypertension in childhood tracks into adulthood and may be associated with increased cardiovascular risk. Studies conducted in children and adolescents provide an opportunity to explore the early cardiovascular target organ injury (CV-TOI) in a population free from many of the co-morbid cardiovascular disease risk factors that confound studies in adults. METHODSYouths (n=132, mean age 15.8 years) were stratified by blood pressure (BP) as low, elevated, and high-BP and by left ventricular mass index (LVMI) as low- and high-LVMI. Systemic circulating RNA, miRNA, and methylation profiles in peripheral blood mononuclear cells and deep proteome profiles in serum were determined using high-throughput sequencing techniques. RESULTSVASH1 gene expression was elevated in youths with high-BP with and without high-LVMI. VASH1 expression levels positively correlated with systolic BP (r=0.3143, p=0.0034). The expression of hsa-miR-335-5p, one of the VASH1-predicted miRNAs, was downregulated in high-BP with high-LVMI youths and was inversely correlated with systolic BP (r=-0.1891, p=0.0489). GSE1 hypermethylation, circulating PROZ upregulation (log2FC=0.61, p=0.0049 and log2FC=0.62, p=0.0064), and SOD3 downregulation (log2FC=-0.70, p=0.0042 and log2FC=-0.64, p=0.010) were observed in youths with elevated BP and high-BP with high-LVMI. Comparing the transcriptomic and proteomic profiles revealed elevated HYAL1 levels in youths displaying high-BP and high-LVMI. CONCLUSIONSThe findings are compatible with a novel blood pressure-associated mechanism that may occur through impaired angiogenesis and extracellular matrix degradation through dysregulation of Vasohibin-1 and Hyaluronidase1 was identified as a possible mediator of CV-TOI in youth with high-BP and suggests strategies for ameliorating TOI in adult-onset primary hypertension.

genomics↗

bioRxiv2022

Adenovirus 14p1 induced changes in miRNA expression increases lung immunopathogenesis

Adenovirus is a frequent cause of mild, usually self-limited infections in infants and young children. Severe infections occur in immunocompromised patients but are rarely observed in healthy, immunocompetent adults. However, there have been outbreaks around the world of infections with different adenoviral (Ad) serotypes that have resulted in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in some of those infected. Ad14p1, the predominant circulating strain of Ad14 worldwide is one such serotype. The explanations for the severity of illness caused by Ad14p1 infection in immunocompetent patients is unknown. Previously, we have shown that A549 cells infected with Ad14 repress macrophage pro29 inflammatory responses whereas cells infected with Ad14p1 fail to repress macrophages and, instead, can increase pro-inflammatory responses. Micro-RNAs (miRNA) are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Adenoviral infection has been shown to modulate host miRNA expression, and we hypothesized that differences in miRNA expression between Ad14 and Ad14p1 infected cells might impact pathogenesis. A549 cells were infected with either Ad14 or Ad14p1 and total RNA samples were collected at 6, 12, 24, 36 and 48 post infection for miRNA sequencing. Cluster analysis revealed that there were 3 temporal changes in miRNA expression profiles following infection. Differential expression analysis showed 8-23 differentially expressed miRNA between Ad14 and Ad14p1 from 6 to 36hpi. However, at 48hpi there were 98 differentially expressed miRNAs in Ad14p1 infected cells compared to those infected by Ad14. Pathway enrichment analysis showed that the differentially expressed miRNA might explain the increased pathogenesis of Ad14p1caused by strain-related loss of modulation of cytokine expression. Overall, the data suggest a role for viral regulation of host miRNA expression in pathogenesis by regulating host inflammatory responses through the delivery of deregulated miRNAs by virally infected cell corpses to macrophages. Author SummaryAcute respiratory distress syndrome (ARDS) is a severe inflammatory disease in the lungs, and both the onset and resolution of ARDS appears to be regulated primarily by alveolar macrophages. Emergent strains of human adenovirus (Ad) can induce ARDS in healthy immunocompetent people, whereas most, common Ad infections go unnoticed or causes minimal symptoms. Why emergent strains of Ad, such as Ad14p1, are more likely to induce acute lung injury (ALI) and ARDS is unknown. Cells that die from wild type Ad14 infection have been shown to repress alveolar macrophage inflammatory responses, whereas cells dying from Ad14p1 infection enhance inflammatory responses of alveolar macrophages. Here, we explored whether virus induced changes in the expression of cellular small regulatory RNAs could explain the differential effects of virally infected cells on alveolar macrophage inflammatory responses. The data show that there are differences in small RNA expression between Ad14 and Ad14p1 infected cells at late times after infection, when Ad14p1 infected cells lose expression of the small RNAs that repress pro-inflammatory cellular signaling pathways in macrophages. Our study provides insights into a mechanism that could drive the increased pathogenesis of some outbreak strains of adenovirus.

microbiology↗