title: MicroRNA network changes in the brain stem underlie the development of hypertension.
abstract: Hypertension 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 well-annotated 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.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Daniel Baugh Institute for Functional Genomics/Computational Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Danielle
authors.initials: D
authors.lastname: DeCicco
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Daniel Baugh Institute for Functional Genomics/Computational Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Haisun
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Daniel Baugh Institute for Functional Genomics/Computational Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brureau
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Daniel Baugh Institute for Functional Genomics/Computational Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: James S
authors.initials: JS
authors.lastname: Schwaber
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Daniel Baugh Institute for Functional Genomics/Computational Biology, Thomas Jefferson University, Philadelphia, Pennsylvania rajanikanth.vadigepalli@jefferson.edu.
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Vadigepalli
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000502:physiology* / Q000503:physiopathology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D006973:Hypertension / Q000235:genetics*; D008297:Male; D035683:MicroRNAs; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D035683:MicroRNAs
keywords: angiotensin II; brain stem; hypertension; microRNA; neuroinflammation