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

• Published in: Acta pharmacologica Sinica 2019-10, Vol.40 (10), p.1322-1333
• Main Authors: Li, Ying, Yang, Li, Dong, Liang, Yang, Zhi-wei, Zhang, Jing, Zhang, Sheng-li, Niu, Meng-jie, Xia, Jing-wen, Gong, Yi, Zhu, Ning, Zhang, Xiu-juan, Zhang, Yuan-yuan, Wei, Xiao-min, Zhang, You-zhi, Zhang, Peng, Li, Sheng-qing
• Format: Article
• Language: English
• Subjects: Activation; Administration, Oral; AKT protein; Animals; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Cell Hypoxia - drug effects; Cell Survival - drug effects; Cells, Cultured; Computational Biology; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Disease Models, Animal; HEK293 Cells; Humans; Hypertension; Hypoxia; Immunoglobulins; Immunology; Immunoprecipitation; Internal Medicine; Kinases; Male; Mass spectrometry; Mass spectroscopy; Medical Microbiology; Muscles; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB protein; Peptidase; Pharmacology/Toxicology; Phosphorylation; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Pulmonary hypertension; Rapamycin; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Sitagliptin Phosphate - administration & dosage; Sitagliptin Phosphate - pharmacology; Smooth muscle; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Transcription; Vaccine; Wound healing; Wound Healing - drug effects
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-019-0272-2

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.