科研之友
微信
新浪微博
Facebook
分享链接
摘要
Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor-gamma (PPAR gamma) are both potential targets for treatment of pulmonary arterial hypertension (PAH). Expression of IP and PPAR gamma decreases in PAH, suggesting that screening of dual agonists of IP and PPAR gamma might be an efficient method for drug discovery. Virtual screening (VS) of potential IP-PPAR gamma 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 PPAR gamma 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 PPAR gamma agonist rosiglitazone. Our results identified cefminox as a dual agonist of IP and PPAR gamma that significantly inhibits PASMC proliferation by up-regulation of PTEN and cAMP, suggesting that it has potential for treatment of PAH.
