The Expression Of Key Enzymes In Mevalonate Pathwav Altered In Pulmonary Artery Tissue Of Monocrotaline-induced Pulmonary Arterial Hypertension Rats

Background:Pulmonary arterial hypertension(PAH)is a vicious pulmonary vascular disease.PAH is defined by mean pulmonary arterial pressure≥25mmHg.The pathological features of PAH are distal pulmonary artery intimal hyperplasia,plexiform lesions,medial hypertrophy,muscle infarction and thrombosis gradually evolved into occlusion of the lumen,high pulmonary arterial pressure and eventually leading to right heart failure.Previous study discovered that the mevalonate pathway plays an important role in cardiovascular remodeling.However,the mevalonate pathway whether participates in PAH development remains unknown.This study aims to investigate the expression pattern about mevalonate pathway related enzymes in monocrotaline(MCT)-induced PAH.Methods:F344 rats were randomly divided into 2 groups(n=6 each):Control group with injecting a single dose of saline;MCT group with injecting a single dose of MCT(60mg/kg).After 4 weeks,the right ventricular systolic pressure(RVSP)was measured and lung and pulmonary artery tissue samples were collected.We detected the expression of enzymes in mevalonate pathway and potential downstream effectors in pulmonary artery tissues.Results:In this study,we found the expression of key enzymes in mevalonate pathway including FDPS,FNTA,GGTase-Ⅰ has a significant increase in pulmonary artery of MCT-induced PAH rats.Meanwhile the small G-protein Racl and RhoA expression were also increased.Furthermore,we detected small G-proteins downstream effectors such as NADPH and ROS and found greater significant increase of ROS and NADPH oxidase activity,while the expression of eNOS protein and serum NO release decreased in PAH group.Conclusion:The expression of key enzyme FDPS,FNTA and GGTase-Ⅰ increased in PAH group,which implied that the mevalonate pathway was involved in PAH pathological development.The potential mechanism may be through regulating Small-G proteins.These findings may provide new potential therapeutic targets for PAH disease.