title: Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension.
abstract: Development of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression. Evaluation of pulmonary arterial endothelial cells and smooth muscle cells revealed that miR-130/301 targeted PPARγ with distinct consequences. In endothelial cells, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling, while in smooth muscle cells, miR-130/301 modulated STAT3-miR-204 signaling to promote PH-associated phenotypes. In murine models, induction of miR-130/301 promoted pathogenic PH-associated effects, while miR-130/301 inhibition prevented PH pathogenesis. Together, these results provide insight into the systems-level regulation of miRNA-disease gene networks in PH with broad implications for miRNA-based therapeutics in this disease. Furthermore, these findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.
authors: Thomas
authors: T
authors: Bertero
authors: Yu
authors: Y
authors: Lu
authors: Sofia
authors: S
authors: Annis
authors: Andrew
authors: A
authors: Hale
authors: Balkrishen
authors: B
authors: Bhat
authors: Rajan
authors: R
authors: Saggar
authors: Rajeev
authors: R
authors: Saggar
authors: W Dean
authors: WD
authors: Wallace
authors: David J
authors: DJ
authors: Ross
authors: Sara O
authors: SO
authors: Vargas
authors: Brian B
authors: BB
authors: Graham
authors: Rahul
authors: R
authors: Kumar
authors: Stephen M
authors: SM
authors: Black
authors: Sohrab
authors: S
authors: Fratz
authors: Jeffrey R
authors: JR
authors: Fineman
authors: James D
authors: JD
authors: West
authors: Kathleen J
authors: KJ
authors: Haley
authors: Aaron B
authors: AB
authors: Waxman
authors: B Nelson
authors: BN
authors: Chau
authors: Katherine A
authors: KA
authors: Cottrill
authors: Stephen Y
authors: SY
authors: Chan
mesh_terms: D000818:Animals; D000073861:Apelin; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D049109:Cell Proliferation; D003198:Computer Simulation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D053263:Gene Regulatory Networks; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D000860:Hypoxia / Q000150:complications; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013598:Systems Theory; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000073861:Apelin; D051792:Basic Helix-Loop-Helix Proteins; D016222:Fibroblast Growth Factor 2; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; D047495:PPAR gamma; D050796:STAT3 Transcription Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; C115436:APLN protein, human; C554019:MIRN130 microRNA, human; C582652:MIRN130 microRNA, mouse; C550735:MIRN301A microRNA, human; C573832:MIRN301 microRNA, mouse; C494173:POU5F1 protein, human