TY - JOUR
T1 - Loss of DP1 aggravates vascular remodeling in pulmonary arterial hypertension via mTORC1 signaling
AU - He, Yuhu
AU - Zuo, Caojian
AU - Jia, Daile
AU - Bai, Peiyuan
AU - Kong, Deping
AU - Chen, Di
AU - Liu, Guizhu
AU - Li, Juanjuan
AU - Wang, Yuanyang
AU - Chen, Guilin
AU - Yan, Shuai
AU - Xiao, Bing
AU - Zhang, Jian
AU - Piao, Lingjuan
AU - Li, Yanli
AU - Deng, Yi
AU - Li, Bin
AU - Roux, Philippe P.
AU - Andreasson, Katrin I.
AU - Breyer, Richard M.
AU - Su, Yunchao
AU - Wang, Jian
AU - Lyu, Ankang
AU - Shen, Yujun
AU - Yu, Ying
N1 - Publisher Copyright:
Copyright © 2020 by the American Thoracic Society
PY - 2020
Y1 - 2020
N2 - Rationale: Vascular remodeling, including smooth muscle cell hypertrophy and proliferation, is the key pathological feature of pulmonary arterial hypertension (PAH). Prostaglandin I2 analogs (beraprost, iloprost, and treprostinil) are effective in the treatment of PAH. Of note, the clinically favorable effects of treprostinil in severe PAH may be attributable to concomitant activation of DP1 (D prostanoid receptor subtype 1). Objectives: To study the role of DP1 in the progression of PAH and its underlying mechanism. Methods: DP1 levels were examined in pulmonary arteries of patients and animals with PAH. Multiple genetic and pharmacologic approaches were used to investigate DP1-mediated signaling in PAH. Measurements and Main Results: DP1 expression was downregulated in hypoxia-treated pulmonary artery smooth muscle cells and in pulmonary arteries from rodent PAH models and patients with idiopathic PAH. DP1 deletion exacerbated pulmonary artery remodeling in hypoxia-induced PAH, whereas pharmacological activation or forced expression of the DP1 receptor had the opposite effect in different rodent models. DP1 deficiency promoted pulmonary artery smooth muscle cell hypertrophy and proliferation in response to hypoxia via induction of mTORC1 (mammalian target of rapamycin complex 1) activity. Rapamycin, an inhibitor of mTORC1, alleviated the hypoxia-induced exacerbation of PAH in DP1-knockout mice. DP1 activation facilitated raptor dissociation from mTORC1 and suppressed mTORC1 activity through PKA (protein kinase A)dependent phosphorylation of raptor at Ser791. Moreover, treprostinil treatment blocked the progression of hypoxia-induced PAH in mice in part by targeting the DP1 receptor. Conclusions: DP1 activation attenuates hypoxia-induced pulmonary artery remodeling and PAH through PKA-mediated dissociation of raptor from mTORC1. These results suggest that the DP1 receptor may serve as a therapeutic target for the management of PAH.
AB - Rationale: Vascular remodeling, including smooth muscle cell hypertrophy and proliferation, is the key pathological feature of pulmonary arterial hypertension (PAH). Prostaglandin I2 analogs (beraprost, iloprost, and treprostinil) are effective in the treatment of PAH. Of note, the clinically favorable effects of treprostinil in severe PAH may be attributable to concomitant activation of DP1 (D prostanoid receptor subtype 1). Objectives: To study the role of DP1 in the progression of PAH and its underlying mechanism. Methods: DP1 levels were examined in pulmonary arteries of patients and animals with PAH. Multiple genetic and pharmacologic approaches were used to investigate DP1-mediated signaling in PAH. Measurements and Main Results: DP1 expression was downregulated in hypoxia-treated pulmonary artery smooth muscle cells and in pulmonary arteries from rodent PAH models and patients with idiopathic PAH. DP1 deletion exacerbated pulmonary artery remodeling in hypoxia-induced PAH, whereas pharmacological activation or forced expression of the DP1 receptor had the opposite effect in different rodent models. DP1 deficiency promoted pulmonary artery smooth muscle cell hypertrophy and proliferation in response to hypoxia via induction of mTORC1 (mammalian target of rapamycin complex 1) activity. Rapamycin, an inhibitor of mTORC1, alleviated the hypoxia-induced exacerbation of PAH in DP1-knockout mice. DP1 activation facilitated raptor dissociation from mTORC1 and suppressed mTORC1 activity through PKA (protein kinase A)dependent phosphorylation of raptor at Ser791. Moreover, treprostinil treatment blocked the progression of hypoxia-induced PAH in mice in part by targeting the DP1 receptor. Conclusions: DP1 activation attenuates hypoxia-induced pulmonary artery remodeling and PAH through PKA-mediated dissociation of raptor from mTORC1. These results suggest that the DP1 receptor may serve as a therapeutic target for the management of PAH.
KW - DP1 receptor
KW - Hypertrophy and proliferation
KW - MTOR signaling
KW - Pulmonary arterial hypertension
KW - Pulmonary artery smooth muscle cell
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U2 - 10.1164/RCCM.201911-2137OC
DO - 10.1164/RCCM.201911-2137OC
M3 - Article
C2 - 31917615
AN - SCOPUS:85084919815
SN - 1073-449X
VL - 201
SP - 1263
EP - 1276
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 10
ER -