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

被引：240

作者：

Bertero, Thomas ^{[1
,2
]}

Cottrill, Katherine A. ^{[1
,2
]}

Lu, Yu ^{[1
,2
]}

Haeger, Christina M. ^{[3
]}

Dieffenbach, Paul ^{[3
]}

Annis, Sofia ^{[1
,2
]}

Hale, Andrew ^{[1
,2
]}

Bhat, Balkrishen ^{[4
]}

Kaimal, Vivek ^{[4
]}

Zhang, Ying-Yi ^{[1
,2
]}

Graham, Brian B. ^{[5
]}

Kumar, Rahul ^{[5
]}

Saggar, Rajan ^{[6
]}

Saggar, Rajeev ^{[7
,8
]}

Wallace, W. Dean ^{[6
]}

Ross, David J. ^{[6
,7
]}

Black, Stephen M. ^{[7
,9
]}

Fratz, Sohrab ^{[10
]}

Fineman, Jeffrey R. ^{[11
]}

Vargas, Sara O. ^{[12
]}

Haley, Kathleen J. ^{[3
]}

Waxman, Aaron B. ^{[3
]}

Chau, B. Nelson ^{[4
]}

Fredenburgh, Laura E. ^{[3
]}

Chan, Stephen Y. ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Cardiovasc Med, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Network Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Pulm & Crit Care Med, Boston, MA 02115 USA

[4] Regulus Therapeut, San Diego, CA 92121 USA

[5] Univ Colorado, Program Translat Lung Res, Denver, CO 80045 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA

[8] Univ Arizona, Dept Med, Phoenix, AZ 85006 USA

[9] Univ Arizona, Dept Med, Tucson, AZ 85724 USA

[10] Klin Tech Univ Munchen, Deutsch Herzzentrum Munchen, Dept Pediat Cardiol & Congenital Heart Dis, D-80636 Munich, Germany

[11] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pediat, San Francisco, CA 94131 USA

[12] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

来源：

CELL REPORTS | 2015年 / 13卷 / 05期

关键词：

ARTERIAL-HYPERTENSION; YAP; MECHANOTRANSDUCTION; MICRORNA-21; SUPPRESSION; ACTIVATION; EXPRESSION; REDUCTION; INHIBITOR; MECHANICS;

D O I：

10.1016/j.celrep.2015.09.049

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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 micro-RNA-130/301 family via activation of the co-transcription factors YAP and TAZ. MicroRNA-130/301 controlled a PPARg-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.

引用

页码：1016 / 1032

页数：17

共 39 条

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