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Cell Rep. 2015 Nov 3;13(5):1016-32. doi: 10.1016/j.celrep.2015.09.049. Epub 2015 Oct 22.

Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit.

Author information

1
Divisions of Cardiovascular and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3
Regulus Therapeutics, San Diego, CA 92121, USA.
4
Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO 80045, USA.
5
Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6
Department of Medicine, University of Arizona, Phoenix, AZ 85006, USA.
7
Department of Medicine, University of Arizona, Tuscon, AZ 85724, USA.
8
Department of Pediatric Cardiology and Congenital Heart Disease, DeutschesHerzzentrum München, Klinik an der Technischen Universität München, 80636 Munich, Germany.
9
Department of Pediatrics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94131, USA.
10
Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
11
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.

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.

PMID:
26565914
PMCID:
PMC4644508
DOI:
10.1016/j.celrep.2015.09.049
[Indexed for MEDLINE]
Free PMC Article

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