10.3389/fphar.2018.00134.s001
Jingwen Xia
Jingwen
Xia
Li Yang
Li
Yang
Liang Dong
Liang
Dong
Mengjie Niu
Mengjie
Niu
Shengli Zhang
Shengli
Zhang
Zhiwei Yang
Zhiwei
Yang
Gulinuer Wumaier
Gulinuer
Wumaier
Ying Li
Ying
Li
Xiaomin Wei
Xiaomin
Wei
Yi Gong
Yi
Gong
Ning Zhu
Ning
Zhu
Shengqing Li
Shengqing
Li
Image1.PDF
Frontiers
2018
hypoxia-induced pulmonary hypertension
prostacyclin receptor
peroxisome proliferator-activated receptor-gamma
phosphatase and tensin homolog
cyclic adenosine monophosphate
2018-02-23 11:37:19
Figure
https://frontiersin.figshare.com/articles/figure/Image1_PDF/5918773
<p>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 (VS) 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.</p>