Cell Reports (Nov 2015)
Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit
- Thomas Bertero,
- Katherine A. Cottrill,
- Yu Lu,
- Christina M. Haeger,
- Paul Dieffenbach,
- Sofia Annis,
- Andrew Hale,
- Balkrishen Bhat,
- Vivek Kaimal,
- Ying-Yi Zhang,
- Brian B. Graham,
- Rahul Kumar,
- Rajan Saggar,
- Rajeev Saggar,
- W. Dean Wallace,
- David J. Ross,
- Stephen M. Black,
- Sohrab Fratz,
- Jeffrey R. Fineman,
- Sara O. Vargas,
- Kathleen J. Haley,
- Aaron B. Waxman,
- B. Nelson Chau,
- Laura E. Fredenburgh,
- Stephen Y. Chan
Affiliations
- Thomas Bertero
- Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Katherine A. Cottrill
- Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Yu Lu
- Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Christina M. Haeger
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Paul Dieffenbach
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Sofia Annis
- Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Andrew Hale
- Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Balkrishen Bhat
- Regulus Therapeutics, San Diego, CA 92121, USA
- Vivek Kaimal
- Regulus Therapeutics, San Diego, CA 92121, USA
- Ying-Yi Zhang
- Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Brian B. Graham
- Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO 80045, USA
- Rahul Kumar
- Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO 80045, USA
- Rajan Saggar
- Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Rajeev Saggar
- Department of Medicine, University of Arizona, Phoenix, AZ 85006, USA
- W. Dean Wallace
- Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- David J. Ross
- Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Stephen M. Black
- Department of Medicine, University of Arizona, Tuscon, AZ 85724, USA
- Sohrab Fratz
- Department of Pediatric Cardiology and Congenital Heart Disease, DeutschesHerzzentrum München, Klinik an der Technischen Universität München, 80636 Munich, Germany
- Jeffrey R. Fineman
- Department of Pediatrics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94131, USA
- Sara O. Vargas
- Department of Pathology, Boston Children’s Hospital, Boston, MA 02115, USA
- Kathleen J. Haley
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Aaron B. Waxman
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- B. Nelson Chau
- Regulus Therapeutics, San Diego, CA 92121, USA
- Laura E. Fredenburgh
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Stephen Y. Chan
- Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- DOI
- https://doi.org/10.1016/j.celrep.2015.09.049
- Journal volume & issue
-
Vol. 13,
no. 5
pp. 1016 – 1032
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 PPARγ-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.
