Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

被引：414

作者：

Bertero, Thomas ^{[1
]}

Oldham, William M. ^{[2
]}

Cottrill, Katherine A. ^{[3
,4
]}

Pisano, Sabrina ^{[1
]}

Vanderpool, Rebecca R. ^{[3
,4
]}

Yu, Qiujun ^{[3
,4
]}

Zhao, Jingsi ^{[3
,4
]}

Tai, Yiyin ^{[3
,4
]}

Tang, Ying ^{[3
,4
]}

Zhang, Ying-Yi ^{[5
]}

Rehman, Sofiya ^{[3
,4
]}

Sugahara, Masataka ^{[3
,4
]}

Qi, Zhi ^{[3
,4
]}

Gorcsan, John, III ^{[3
,4
]}

Vargas, Sara O. ^{[6
]}

Saggar, Rajan ^{[7
,8
]}

Saggar, Rajeev ^{[9
]}

Wallace, W. Dean

Ross, David J. ^{[7
,8
]}

Haley, Kathleen J. ^{[2
,7
,8
]}

Waxman, Aaron B. ^{[2
]}

Parikh, Victoria N. ^{[10
]}

De Marco, Teresa ^{[11
]}

Hsue, Priscilla Y. ^{[11
]}

Morris, Alison ^{[12
]}

Simon, Marc A. ^{[3
,4
]}

Norris, Karen A. ^{[13
]}

Gaggioli, Cedric ^{[1
]}

Loscalzo, Joseph ^{[5
,14
]}

Fessel, Joshua ^{[15
]}

Chan, Stephen Y. ^{[3
,4
]}

机构：

[1] Univ Nice Sophia Antipolis, Sch Med, IRCAN, CNRS,INSERM,U1081,UMR7284, Nice, France

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

[3] Univ Pittsburgh, Sch Med, Dept Med,Div Cardiol, Ctr Pulm Vasc Biol & Med,Pittsburgh Heart Lung Bl, Pittsburgh, PA 15261 USA

[4] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15261 USA

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

[6] Boston Childrens Hosp, Dept Pathol, Boston, MA USA

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

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

[9] Univ Arizona, Dept Med, Phoenix, AZ USA

[10] Stanford Univ, Dept Med, Div Cardiol, Palo Alto, CA 94304 USA

[11] UCSF, Dept Med, Div Cardiol, San Francisco, CA USA

[12] Univ Pittsburgh, Med Ctr, Dept Med, Div Pulm & Crit Care Med, Pittsburgh, PA 15261 USA

[13] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15261 USA

[14] Harvard Med Sch, Lab Syst Pharmacol, Boston, MA USA

[15] Vanderbilt Univ, Med Ctr, Dept Med, Div Pulm & Crit Care Med, Nashville, TN USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2016年 / 126卷 / 09期

关键词：

TO-MESENCHYMAL TRANSITION; ARTERIAL-HYPERTENSION; RIGHT VENTRICLE; METABOLISM; PATHWAY; YAP; PROLIFERATION; GLUTAMINASE; INHIBITION; MECHANICS;

D O I：

10.1172/JCI86387

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus-infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ-GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.

引用

页码：3313 / 3335

页数：23

共 55 条

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