Osthole attenuates pulmonary arterial hypertension by the regulation of sphingosine 1-phosphate in rats  

作　　者：YAO Li YANG Yu-Xia CAO Hui REN Huan-Huan NIU Zheng SHI Ling 

机构地区：[1]Department of Medicinal Chemistry and Natural Medicine Chemistry,Department of Pharmacognosy,College of Pharmacy,Harbin Medical University,Harbin 150081,China [2]State-Province Key Laboratory of Biomedicine-Pharmaceutics of China,Harbin Medical University,Harbin 150081,China [3]Department of Pharmacology,College of Pharmacy,Harbin Medical University,Harbin 150081,China

出　　处：《Chinese Journal of Natural Medicines》2020年第4期308-320,共13页中国天然药物（英文版）

基　　金：the National Natural Science Foundation of China Grants (No. 81302764);the Science and Technology Grant for Excellent Talents of Harbin (No.2017RAXXJ060)。

摘　　要：Osthole is observed to have the capacity to treat pulmonary arterial hypertension(PAH) in rats, but molecular mechanism is still unknown. The present study aims to discover therapeutic targets and explore therapeutic mechanism of osthole against PAH from metabolic perspective. A rat model with PAH was successfully established with MCT, following osthole administration, then untargeted metabolomics assay was performed using UPLC-Q-TOF-MS to identify differential metabolites and associated metabolic pathways, at last mechanism investigation was done by qRT-PCR, Western blot and ELISA. Differential metabolites characterized in rats with PAH were mostly assigned to sphingolipid metabolism, synthesis of unsaturated fatty acids, glycolysis, nucleotide metabolism, steroid hormone biosynthesis. Furthermore, osthole reversed high level of S1 P by modulating metabolic enzyme Sphk1 in rats with PAH. In addition, osthole inhibited the expression of Sphk1 by downregulating microRNA-21, phosphorylation of Akt, phosphorylation of mTOR in vivo and in vitro. These results demonstrated that metabolomics is a promising approach to discover potential drug target for PAH treatment. Importantly, our findings further elucidated therapeutic mechanism of osthole, a natural product, having a role of metabolic regulator to potentially treat PAH by targeting inhibition of Sphk1/S1 P via microRNA-21-PI3 K/Akt/mTOR signal pathway. Altogether, this discovery paves a critical foundation for enabling osthole to be a candidate compound to treat PAH.

关 键 词：Pulmonary arterial hypertension OSTHOLE Metabolomics Sphk1/S1P MicroRNA-21-PI3K/Akt/mTOR Therapeutic mechanism 

分 类 号：R965[医药卫生—药理学]