title: Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit.
abstract: Pulmonary hypertension (PH) is a deadly vascular disease with enigmatic molecular origins. We found that vascular extracellular matrix (ECM) remodeling and stiffening are early and pervasive processes that promote PH. In multiple pulmonary vascular cell types, such ECM stiffening induced the microRNA-130/301 family via activation of the co-transcription factors YAP and TAZ. MicroRNA-130/301 controlled a PPAR?-APOE-LRP8 axis, promoting collagen deposition and LOX-dependent remodeling and further upregulating YAP/TAZ via a mechanoactive feedback loop. In turn, ECM remodeling controlled pulmonary vascular cell crosstalk via such mechanotransduction, modulation of secreted vasoactive effectors, and regulation of associated microRNA pathways. In vivo, pharmacologic inhibition of microRNA-130/301, APOE, or LOX activity ameliorated ECM remodeling and PH. Thus, ECM remodeling, as controlled by the YAP/TAZ-miR-130/301 feedback circuit, is an early PH trigger and offers combinatorial therapeutic targets for this devastating disease.
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertero
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Cottrill
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Haeger
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Dieffenbach
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Annis
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hale
authors.affiliation: Regulus Therapeutics, San Diego, CA 92121, USA.
authors.forename: Balkrishen
authors.initials: B
authors.lastname: Bhat
authors.affiliation: Regulus Therapeutics, San Diego, CA 92121, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kaimal
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO 80045, USA.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Graham
authors.affiliation: Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO 80045, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Saggar
authors.affiliation: Department of Medicine, University of Arizona, Phoenix, AZ 85006, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Saggar
authors.affiliation: Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: W Dean
authors.initials: WD
authors.lastname: Wallace
authors.affiliation: Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Ross
authors.affiliation: Department of Medicine, University of Arizona, Tuscon, AZ 85724, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.affiliation: Department of Pediatric Cardiology and Congenital Heart Disease, DeutschesHerzzentrum München, Klinik an der Technischen Universität München, 80636 Munich, Germany.
authors.forename: Sohrab
authors.initials: S
authors.lastname: Fratz
authors.affiliation: Department of Pediatrics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94131, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Sara O
authors.initials: SO
authors.lastname: Vargas
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Haley
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Waxman
authors.affiliation: Regulus Therapeutics, San Diego, CA 92121, USA.
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: chansy@pitt.edu.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Chan
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D026502:LDL-Receptor Related Proteins; D035683:MicroRNAs; D047495:PPAR gamma; D014157:Transcription Factors; C098773:low density lipoprotein receptor-related protein 8