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The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension.

ABSTRACT: Pulmonary hypertension (PH) is a complex disorder, spanning several known vascular cell types. Recently, we identified the microRNA-130/301 (miR-130/301) family as a regulator of multiple pro-proliferative pathways in PH, but the true breadth of influence of the miR-130/301 family across cell types in PH may be even more extensive. Here, we employed targeted network theory to identify additional pathogenic pathways regulated by miR-130/301, including those involving vasomotor tone. Guided by these predictions, we demonstrated, via gain- and loss-of-function experimentation in vitro and in vivo, that miR-130/301-specific control of the peroxisome proliferator-activated receptor ? regulates a panel of vasoactive factors communicating between diseased pulmonary vascular endothelial and smooth muscle cells. Of these, the vasoconstrictive factor endothelin-1 serves as an integral point of communication between the miR-130/301-peroxisome proliferator-activated receptor ? axis in endothelial cells and contractile function in smooth muscle cells. Thus, resulting from an in silico analysis of the architecture of the PH disease gene network coupled with molecular experimentation in vivo, these findings clarify the expanded role of the miR-130/301 family in the global regulation of PH. They further emphasize the importance of molecular cross-talk among the diverse cellular populations involved in PH.

SUBMITTER: Bertero T

PROVIDER: S-EPMC4303661 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension.

Bertero Thomas T Cottrill Katherine K Krauszman Adrienn A Lu Yu Y Annis Sofia S Hale Andrew A Bhat Balkrishen B Waxman Aaron B AB Chau B Nelson BN Kuebler Wolfgang M WM Chan Stephen Y SY

The Journal of biological chemistry 20141212 4

Pulmonary hypertension (PH) is a complex disorder, spanning several known vascular cell types. Recently, we identified the microRNA-130/301 (miR-130/301) family as a regulator of multiple pro-proliferative pathways in PH, but the true breadth of influence of the miR-130/301 family across cell types in PH may be even more extensive. Here, we employed targeted network theory to identify additional pathogenic pathways regulated by miR-130/301, including those involving vasomotor tone. Guided by the ...[more]

PMID: 25505270

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Project description:Purpose: Guided by an in silico combination of microRNA (miRNA) target prediction, analysis of transcriptomic changes in 137 human diseases, and advanced gene network modeling, we predicted the miR-130/301 family of miRNAs as a shared regulator of a fibrotic gene network across human diseases, thus orchestrating broad control over disease manifestation. The goals of this study are to compare the lung mRNA profile of mouse model of Pulmonary hypertension, one of the most fibrotic pathology uncovered by our in silico prediction, treated with an inhibitor of miR-130/301 (Short-130) to mice treated with a control inhibitor (Short-NC). Methods: Eight-week-old mice (C57BL/6) were injected with SU5416 (20 mg/kg/dose; Sigma-Aldrich), followed by exposure to normobaric hypoxia (10% O2; OxyCycler chamber, Biospherix Ltd.) for 2 weeks. After 2 weeks and confirmation of PH development in 5 mice (right heart catheterization), mice were further treated with 3 intrapharyngeal injections (every 4 days) of control or miR-130/301 shortmer oligonucleotides, designed as fully modified antisense oligonucleotides complementary to the seed sequence of the miR-130/301 miRNA family (10 mg/kg/dose; Regulus). Specifically, the control and miR-130/301 shortmer oligonucleotides were nontoxic, lipid-permeable, high-affinity oligonucleotides. The miR-130/301 shortmer carried a sequence complementary to the active site of the miR-130/301 miRNA family, containing a phosphorothioate backbone and modifications (fluoro-, methoxyethyl, and bicyclic sugar) at the sugar 2’ position. Three days after the last injection, right heart catheterization was performed followed by harvesting of lung tissue for RNA extraction. Lung mRNA profiles of those mice or control mice (Normoxia+SU5416) were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000. The sequence reads that passed quality filters were analyzed at the gene-level count. The gene level counts were then normalized with the R/Bioconductor package limma using the voom /variance stabilization method. The data were quality controlled for outliers using principal component analysis (PCA). Differential expression analysis between transcriptome profiles of experimental groups was performed using the R / Bioconductor package limma. Results: Transcriptomic analyses of whole lung from mice with hypoxia+SU5416-induced PH revealed a generalized de-repression of miR-130/301 targets by Short-130 treatment. Importantly, although whole lung transcriptomics likely captured only a subset of the miR-130/301 targets affecting the diseased pulmonary vasculature, pathway enrichment nonetheless revealed pronounced representation of several pathways known to be involved in fibrosis. Thus, the miR-130/301 family indeed induces a programmatic shift at the molecular level toward the fibrotic pathophenotype in vivo

Dataset Information

The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension.

Publications

The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension.

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