Crosstalk between the Akt/mTORC1 and NF-κB signaling pathways promotes hypoxia-induced pulmonary hypertension by increasing DPP4 expression in PASMCs

Authors: Ying Li1,2, Li Yang3, Liang Dong1, Zhi-wei Yang4, Jing Zhang1, Sheng-li Zhang4, Meng-jie Niu5, Jing-wen Xia1, Yi Gong1, Ning Zhu1, Xiu-juan Zhang1, Yuan-yuan Zhang1, Xiao-min Wei1, You-zhi Zhang1, Peng Zhang1, Sheng-qing Li1
1 Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
2 Department of Respiratory Medicine, Shaanxi Provincial Second People’s Hospital, Xi’an 710005, China
3 Department of Anesthesiology, Grade 2014, Chongqing Medical University, Chongqing 400016, China
4 Department of Applied Physics, Xi’an Jiaotong University, Xi’an 710049, China
5 Department of Gastroenterology Medicine, Xi’an Third Hospital, Xi’an 710018, China
Correspondence to: Sheng-qing Li:,
DOI: 10.1038/s41401-019-0272-2
Received: 1 February 2019
Accepted: 11 June 2019
Advance online: 17 July 2019


Abnormal wound healing by pulmonary artery smooth muscle cells (PASMCs) promotes vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Increasing evidence shows that both the mammalian target of rapamycin complex 1 (mTORC1) and nuclear factor-kappa B (NF-κB) are involved in the development of HPH. In this study, we explored the crosstalk between mTORC1 and NF-κB in PASMCs cultured under hypoxic condition and in a rat model of hypoxia-induced pulmonary hypertension (HPH). We showed that hypoxia promoted wound healing of PASMCs, which was dose-dependently blocked by the mTORC1 inhibitor rapamycin (5−20 nM). In PASMCs, hypoxia activated mTORC1, which in turn promoted the phosphorylation of NF-κB. Molecular docking revealed that mTOR interacted with IκB kinases (IKKs) and that was validated by immunoprecipitation. In vitro kinase assays and mass spectrometry demonstrated that mTOR phosphorylated IKKα and IKKβ separately. Inhibition of mTORC1 decreased the level of phosphorylated IKKα/β, thus reducing the phosphorylation and transcriptional activity of NF-κB. Bioinformatics study revealed that dipeptidyl peptidase-4 (DPP4) was a target gene of NF-κB; DPP4 inhibitor, sitagliptin (10−500 μM) effectively inhibited the abnormal wound healing of PASMCs under hypoxic condition. In the rat model of HPH, we showed that NF-κB activation (at 3 weeks) was preceded by mTOR signaling activation (after 1 or 2 weeks) in lungs, and administration of sitagliptin (1−5 mg/kg every day, ig) produced preventive effects against the development of HPH. In conclusion, hypoxia activates the crosstalk between mTORC1 and NF-κB, and increased DPP4 expression in PASMCs that leads to vascular remodeling. Sitagliptin, a DPP4 inhibitor, exerts preventive effect against HPH.
Keywords: pulmonary hypertension; mTORC1; NF-κB; IκB kinase; DPP4; sitagliptin; pulmonary artery smooth muscle cells

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