MicroRNA network changes in the brain stem underlie the development of hypertension

Abstract

sion is a major chronic disease whose molecular mechanisms remain poorly understood. We compared neuroanatomical patterns of microRNAs in the brain stem of the spontaneous hypertensive rat (SHR) to the Wistar Kyoto rat (WKY, control). We quantified 419 wellannotated microRNAs in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), from SHR and WKY rats, during three main stages of hypertension development. Changes in microRNA expression were stage-and region-dependent, with a majority of SHR vs. WKY differential expression occurring at the hypertension onset stage in NTS versus at the prehypertension stage in RVLM. Our analysis identified 24 microRNAs showing time-dependent differential expression in SHR compared with WKY in at least one brain region. We predicted potential gene regulatory targets corresponding to catecholaminergic processes, neuroinflammation, and neuromodulation using the miRWALK and RNA22 databases, and we tested those bioinformatics predictions using high-throughput quantitative PCR to evaluate correlations of differential expression between the microRNAs and their predicted gene targets. We found a novel regulatory network motif consisting of microRNAs likely downregulating a negative regulator of prohypertensive processes such as angiotensin II signaling and leukotriene-based inflammation. Our results provide new evidence on the dynamics of microRNA expression in the development of hypertension and predictions of microRNA-mediated regulatory networks playing a region-dependent role in potentially altering brain-stem cardiovascular control circuit function leading to the development of hypertension.hypertension; microRNA; neuroinflammation; angiotensin II; brain stem HYPERTENSION IS A MAJOR CHRONIC disease worldwide, affecting about 50 million adults in the United States alone. It is a multiorgan disease and a major cause of heart failure, coronary heart disease, atrial fibrillation, stroke, and end-stage renal disease, and it has an enormous economic impact. About 90 -95% of cases are "essential" with no known medical cause (11). Moreover, only about a third of hypertensive patients have their blood pressure fully controlled (11). A significant and increasing population (ϳ25%) of hypertensive patients is drug resistant. There remains an unmet need for antihypertensive therapy.In the context of the recent discovery of novel lines of therapeutic interventions involving approaches to modulate microRNA we decided to elucidate changes in microRNA levels during the development of spontaneous hypertensive rat (SHR) hypertension. The recent explosion in microRNA research has produced new computational and experimental approaches for studying microRNA functions in cell culture and in vivo, which we take advantage of here. MicroRNAs are an abundant class of small (ϳ22 nt) endogenous noncoding RNAs that direct posttranscriptional regulation of gene expression. There is ample evidence that dysregulation of microRNAs is associated with the pathogenesis of human diseases, in...

Systemic leukotriene B4 receptor antagonism lowers arterial blood pressure and improves autonomic function in the spontaneously hypertensive rat

“…Methods previously used for sample acquisition were followed (DeCicco et al . ). Briefly, male, Wistar Kyoto (WKY/NHsd) rats and spontaneous hypertensive rats (SHR/NHsd) obtained from Harlan Laboratories were housed one per cage in the Thomas Jefferson University (TJU) animal facility.…”

“…For qPCR analysis, significance of gene expression differences between SHR and WKY at each time point was evaluated by a Tukey's post hoc honest significant difference approach using aov and Tukey HSD functions in the core statistical package of the R platform (DeCicco et al . ; R Core Team, ).…”

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“…We followed the methods we have previously utilized for NanoString ™ data analysis (31). NanoString ™ data set has endogenous controls and RNA spike-ins, i.e., additional negative controls from other species purposefully added to the assay to assure that reads were not from non-specific binding.…”

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“…Divergent molecular networks have been associated with cardiovascular disease and aberrant ANS function [40, 79]. Such connectivity differences reflect re-wiring of the molecular networks that determine the gene regulatory interaction dynamics which underly cell, tissue, and organismal physiology [80].…”