Protective Effects Of STV-Na On Rats With Pulmonary Arterial Hypertension Induced By Monocrotaline And Study Of The Underlying Molecular Mechanisms

Pulmonary arterial hypertension(PAH)is a syndrome characterized by an elevation of mean pulmonary arterial pressure,normally above 25 mmHg.The pathological mechanism of PAH is complicated.Although an improved understanding of the pathophysiology of the disease has resulted in the development of effective therapies,PAH remains an irreversible disease.Novel treatments are required to treat or prevent the progression of PAH.STV-Na is the sodium salt form of Isosteviol(STV),which is is an acid hydrolysate of stevioside.Many reports have demonstrated that STV-Na has exhibited anti-inflammatory and antioxidative effects,which can alleviate the ischemia-reperfusion induced cardiac injuries.Although STV-Na has protective cardiovascular effects,whether STV-Na has effects on PAH has never been reported.The aim of this study was to investigate the protective effect and the underlying mechanism of STV-Na on PAH.The main contents include the following parts:(1)First,we studied whether STV-Na had the protective effect of PAH on rats: SD rats were given a single intraperitoneal injection of 60 mg/kg MCT to induce PAH.Thirty-four SD rats were divided into three groups: Control,PAH,PAH treatment groups.For the PAH treatment group,STV-Na was administrated intragastrically at 5 mg/kg/day,while control and PAH groups were treated with the same amount of 0.9% saline.4 weeks later,the main hemodynamic parameters of rats,especially mRVP and RVSP,were measured by right cardiac catheter;and the histological experiments were performed to analyse medial thickness,collagen deposition of pulmonary arterioles and the right ventricular hypertrophy.(2)We decided to analyse the underlying mechanism of STV-Na from right ventricle and lung: mRNA associated with fatty acid metabolism including CD36?PPAR??PPAR??CPT1 were measured in the right ventricle;Other factors related with oxidative stress including the levels of MDA,Nox-4 and NO were also measured in the lung.The results indicated that:(1)The mRVP of the PAH was 36.4 ± 2.3 mmHg,which was significantly higher than that of control(p < 0.01)and STV-Na treatment(p < 0.05).The RVSP of the PAH was 77.6 ± 5.9 mmHg,which was significantly higher than that of control(p < 0.01).While the RVSP of the STV-Na treatment(64.4 ± 3.7 mmHg)was not significantly lower than PAH.(2)The results of histological experiments showed that compared with control,the medial thickness,collagen deposition of pulmonary arterioles and the right ventricular hypertrophy were significantly higher(p < 0.01),and STV-Na treatment could significantly alleviate these changes(p < 0.01).(3)The results of underlying mechanism of STV-Na showed that STV-Na could not have significant effects on mRNA associated with fatty acid metabolism in the right ventricle;But the results of other factors related with oxidative stress in the lung showed that compared with control,the levels of MDA and Nox-4 were significantly higher(p < 0.01),and STV-Na treatment could significantly improve these changes.Meanwhile,STV-Na could also increase the production of NO(p < 0.05).In the current research,we examined the protective effects of STV-Na on PAH and the possible underlying mechanisms.Our results showed that STV could alleviate symptoms of PAH,possibly through decreasing oxidative stress resulted from Nox-4 and improving the production of NO.The study is potentially useful for the development of new drugs for PAH.