Fullerenol Improves Monocrotaline-induced Pulmonary Hypertension And Right Ventricular Remodeling In Rats

Research background and purpose:pulmonary arterial hypertension(PAH)is a chronic progressive disease caused by a variety of etiologies and pathogenesis,which leads to increased pulmonary vascular resistance,right heart failure and even death.However,clinical anti-pulmonary hypertension drugs are expensive and has poor therapeutic effect on patients with advanced PAH.The occurrence and development of PAH is closely related to oxidative stress injury.Therefore,it is necessary to explore new anti-oxidative stress drugs to reduce pulmonary arterial pressure.Fullerenol(FUL),a new carbon nanomaterial known as "free radical sponge",is a powerful and effective antioxidant drug.FUL has strong water solubility and high biocompatibility.A molecule of FUL can combine with a little of reactive oxygen species(ROS).This study aims to explore the effects of FUL on monocrotaline(MCT)-induced pulmonary hypertension and right ventricular remodeling in rats.Materials and Methods:Ten male Sprague-Dawley(SD)rats were randomLy selected as the Control group,and the remaining rats were intraperitoneally injected with 1%MCT(60 mg/kg)to establish PAH model.after one week,10 models rats were randomLy selected to inject with 10 mg/kg FUL for 14 days.During the experiment,the general condition of the rats was observed and recorded.Mean pulmonary arterial pressure(mPAP)was measured by right ventricular catheter test,and the right ventricular hypertrophy index(RVHI)and whole-heart/body index were calculated.H&E staining was used to observe the pathological changes of pulmonary vessels and right ventricular.Vascular wall thickness ratio(WT%)and vascular wall area ratio(WA%)were measured.Masson staining was used to observe collagen deposition in pulmonary vessels,pulmonary tissue and right ventricular.The expression of α-smooth muscle actin(α-SMA)in pulmonary tissue were determined by immunohistochemical staining.Serum brain natriuretic peptide(BNP),tumor necrosis factor-α(TNF-α),and interleukin-6(IL-6)levels were measured by ELISA.The serum ROS content was determined by colorimetry.Serum superoxide dismutase(SOD)activity was measured by WST-1.The content of malondialdehyde(MDA)in serum was determined by TBA.Nuclear factor erythroid 2-related factor 2(Nrf2)、Heme Oxygenase-1(HO-1)、B-cell lymphoma-2 protein(Bcl-2)and Bcl2associated X(Bax)were detected by western blotting(WB).Result:1.Compared with the control group,rats’ weight in the MCT group was decreased,and rats’ mPAP was increased by 88.4%(P<0.05).the weight of rats in the MCT+FUL group was not significantly recovered(P>0.05),but mPAP was decreased by 34.8%(P<0.05).2.Compared with the control group,WT%and WA%in the MCT group were increased(P<0.05).The thickness of pulmonary artery and the degree of lumen stenosis was aggravated.The pulmonary artery and pulmonary tissue were extensively deposition of blue collagen fibers,and were full of inflammatory cells.The expression of α-SMA in pulmonary artery was significantly increased.WT%and WA%were decreased in MCT+FUL group compared with MCT group(P<0.05).The thickness of pulmonary artery,lumen stenosis,pulmonary tissue consolidation and inflammatory cell were reduced,and the expression of α-SMA was decreased.3.Compared with the control group,RVHI and whole-heart/body weight ratio in MCT group were significantly increased(P<0.05).Pathological staining indicated swelling of myocardial cells,nuclear shrinkage and deformation,infiltration of inflammatory cells,rupture of myocardial fibers,and deposition of a small amount of collagen fibers.RVHI and whole-heart/body weight ratio were decreased in MCT+FUL group(P<0.05),myocardial cell swelling,nuclear deformation,muscle fiber breakage and inflammatory cell infiltration were reduced,and collagen fiber deposition was not obvious.4.Compared with Control group,the levels of serum BNP,ROS,MDA,TNF-α and IL-6 were increased(P<0.05),while the content of SOD was decreased(P<0.05).The serum levels of BNP,ROS,MDA,TNF-α and IL-6 in MCT+FUL group were lower than those in MCT group(P<0.05),while the SOD content in MCT+FUL group was higher than that in MCT group(P<0.05).5.It was found that Nrf2,HO-1 and Bcl-2 in the MCT group were significantly down-regulated by WB(P<0.05),while Bax was up-regulated(P<0.05).Compared with MCT group,Nrf2,HO-1 and Bcl-2 proteins in MCT+FUL group were increased,while Bax was decreased(P<0.05).Conclusion:1.FUL can alleviate mPAP of MCT-induced rats,the thickness of pulmonary artery,collagen fiber deposition in pulmonary artery,surrounding pulmonary tissue and the degree of pulmonary artery muscle normalization.2.FUL showed anti-oxidative stress and anti-inflammatory effects in PAH rats.3.FUL alleviated the degree of right ventricular hypertrophy in MCT-induced PAH rats and reduced the level of BNP,an indicator of heart failure.4.FUL may protect the right ventricular through Nrf2/HO-1 pathway.FUL can increase the express of Bcl-2 and decrease the express of Bax in right ventricular.