title: 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 γ 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 γ 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.
authors.affiliation: From the Divisions of Cardiovascular and Network Medicine and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertero
authors.affiliation: From the Divisions of Cardiovascular and Network Medicine and.
authors.forename: Katherine
authors.initials: K
authors.lastname: Cottrill
authors.affiliation: the Keenan Research Centre for Biomedical Science of St. Michael's, University of Toronto, Toronto, Ontario M5R 0A3, Canada.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Krauszman
authors.affiliation: From the Divisions of Cardiovascular and Network Medicine and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: From the Divisions of Cardiovascular and Network Medicine and.
authors.forename: Sofia
authors.initials: S
authors.lastname: Annis
authors.affiliation: From the Divisions of Cardiovascular and Network Medicine and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hale
authors.affiliation: Regulus Therapeutics, San Diego, California 92121, and.
authors.forename: Balkrishen
authors.initials: B
authors.lastname: Bhat
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Waxman
authors.affiliation: Regulus Therapeutics, San Diego, California 92121, and.
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
authors.affiliation: the Keenan Research Centre for Biomedical Science of St. Michael's, University of Toronto, Toronto, Ontario M5R 0A3, Canada, the Department of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.affiliation: From the Divisions of Cardiovascular and Network Medicine and sychan@partners.org.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Chan
mesh_terms: D000465:Algorithms; D000818:Animals; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D047495:PPAR gamma / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism; D015398:Signal Transduction; D049490:Systems Biology; D014661:Vasoconstriction
chemical_list: D019332:Endothelin-1; D016232:Endothelins; C554019:MIRN130 microRNA, human; C550735:MIRN301A microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; D047495:PPAR gamma
keywords: Endothelial Cell; Endothelin; MicroRNA (miRNA); Pulmonary Hypertension; Pulmonary Vasomotor Tone; Systems Biology; Vascular Smooth Muscle Cells