Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit.
Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit.
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DOI：
10.1016/j.celrep.2015.09.049
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发表时间：
2015-11-03
期刊：
影响因子：
8.8
通讯作者：
Chan SY
中科院分区：
文献类型：
--
作者：
Bertero T;Cottrill KA;Lu Y;Haeger CM;Dieffenbach P;Annis S;Hale A;Bhat B;Kaimal V;Zhang YY;Graham BB;Kumar R;Saggar R;Saggar R;Wallace WD;Ross DJ;Black SM;Fratz S;Fineman JR;Vargas SO;Haley KJ;Waxman AB;Chau BN;Fredenburgh LE;Chan SY
肺动脉高压（PH）是一种致命的血管疾病，其分子起源尚不清楚。我们发现，血管细胞外基质（ECM）重塑和硬化是早期和普遍的过程，促进PH。在多种肺血管细胞类型，这样的ECM硬化诱导microRNA-130/301家族通过激活共转录因子雅普/TAZ。MicroRNA-130/301控制着一个PPARγ-APOE-LRP 8轴，促进胶原沉积和LOX依赖性重塑，并通过机械活性反馈环进一步上调雅普/TAZ。反过来，ECM重塑控制肺血管细胞串扰通过这样的机械转导，分泌的血管活性效应器的调制，和相关的microRNA途径的调节。在体内，microRNA-130/301、APOE或LOX活性的药理学抑制改善了ECM重塑和PH。因此，由雅普/TAZ-miR-130/301反馈回路控制的ECM重塑是早期PH触发物，并为这种破坏性疾病提供了组合治疗靶点。
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 co-transcription factors YAP/TAZ. MicroRNA-130/301 controlled a PPARγ-APOE-LRP8 axis, promoting collagen deposition and LOX-dependent remodeling and further up-regulating 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.