Loss of DP1 Aggravates Vascular Remodeling in Pulmonary Arterial Hypertension Via mTORC1 Signaling

作者：Yuhu He, Caojian Zuo, Daile Jia, Peiyuan Bai, Deping Kong, Di Chen, Guizhu Liu, Juanjuan Li, Yuanyang Wang, Guilin Chen, Shuai Yan, Bing Xiao, Jian Zhang, Lingjuan Piao, Yanli Li, Yizhen Deng, Bin Li, Philippe P. Roux, Katrin I. Andreasson, Richard Breyer, Yunchao Su, Jian Wang, Ankang Lyu, Yujun Shen, Ying Yu · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2020 · DOI：10.1164/rccm.201911-2137oc · 被引用次数：79 · 研究领域：Pulmonary Hypertension Research and Treatments、PI3K/AKT/mTOR signaling in cancer

Abstract 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 m...