Original Research ARTICLE
Cefminox, a dual agonist of prostacyclin receptor and peroxisome proliferator-activated receptor-gamma identified by virtual screening, has therapeutic efficacy against hypoxia-induced pulmonary hypertension in rats
- 1Department of Pulmonary and Critical Care Medicine, Huashan Hospital Affiliated to Fudan University, China
- 2Department of Gastroenterology Medicine, Xi'an No.3 Hospital, China
- 3Department of Applied Physics, Xi'an Jiaotong University, China
- 4Department of Respiratory Medicine, Shaanxi Provincial Second People’s Hospital, China
Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor-gamma (PPARγ) are both potential targets for treatment of pulmonary arterial hypertension (PAH). Expression of IP and PPARγ decreases in PAH, suggesting that screening of dual agonists of IP and PPARγ might be an efficient method for drug discovery. Virtual screening of potential IP–PPARγ dual-targeting agonists was performed in the ZINC database. Ten of the identified compounds were further screened, and cefminox was found to dramatically inhibit growth of PASMCs with no obvious cytotoxicity. Growth inhibition by cefminox was partially reversed by both the IP antagonist RO113842 and the PPARγ antagonist GW9662. Investigation of the underlying mechanisms of action demonstrated that cefminox inhibits the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway through up-regulation of the expression of phosphatase and tensin homolog (PTEN, which is inhibited by GW9662), and enhances cyclic adenosine monophosphate (cAMP) production in PASMCs (which is inhibited by RO113842). In a rat model of hypoxia-induced pulmonary hypertension, cefminox displayed therapeutic efficacy not inferior to that of the prostacyclin analog iloprost or the PPARγ agonist rosiglitazone. Our results identified cefminox as a dual agonist of IP and PPARγ that significantly inhibits PASMC proliferation by up-regulation of PTEN and cAMP, suggesting that it has potential for treatment of PAH.
Keywords: hypoxia-induced pulmonary hypertension, prostacyclin receptor, peroxisome proliferator-activated receptor-gamma, Phosphatase and tensin homolog, cyclic adenosine monophosphate
Received: 24 Nov 2017;
Accepted: 07 Feb 2018.
Edited by:Jianfeng Pei, Peking University, China
Reviewed by:Qinghua Hu, Tongji Medical College, Huazhong University of Science and Technology, China
Lina Ding, Zhengzhou University, China
Zhichao LI, Fourth Military Medical University, China
Copyright: © 2018 Li, Xia, Dong, Niu, Zhang, Yang, Li, Wei, Gong and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Shengqing Li, Huashan Hospital Affiliated to Fudan University, Department of Pulmonary and Critical Care Medicine, Shanghai, China, email@example.com