Sevoflurane Attenuates Pulmonary Vascular Remodeling And Right Ventricular Dysfunction In Pulmonary Arterial Hypertension Via NF-κB And MAPK Pathway

Objective:Pulmonary arterial hypertension(PAH)is a life-threatening cardiovascular disorder disease characterized by progressive pulmonary vasoconstriction leading to pulmonary vascular remodeling,and causes right ventricular hypertrophy(RVH)leading to right ventricular failure(RVF)eventually.Despite the pathophysiology of PAH has been increasingly recognized,its mortality remains high when RVF develops.Pulmonary vascular remodeling is one of the important pathophysiological mechanisms of PAH,which leading to intraluminal narrowing and even occlusion,the afterload of right ventricle(RV)increasing and the structure and function of RV changes.Pulmonary arterial endothelial cells dysfunction,inflammation and oxidative stress are three key mechanisms responsible for the remodeling of vessels,and the interactions of these three components participate in the transformation of the RV from the compensatory to the loss.Nuclear factor-κB(NF-κB)and mitogen-activated protein kinase(MAPK)signaling pathway,as the main inflammatory and oxidative stress pathways,are closely related to PAH,so therapeutic approaches targeting NF-κB,MAPK and their downstream mediums can reduce the morbidity and mortality of PAH.Cardioprotective properties of volatile anesthetics,represented by sevoflurane,have been recognized in preclinical and clinical studies,however,most studies based on left ventricular(LV)diseases such as ischemia and reperfusion injury,whether this volatile drug has beneficial effects in RV remains unclear.On the other hand,the anti-inflammatory and anti-oxidative stress functions of sevoflurane have been widely studied in several areas.Therefore,the main aim of this study is to investigated the effect of sevoflurane on pulmonary vascular remodeling and RV dysfunction in MCT-induced rat model of PAH,and the role of inflammatory,oxidative stress,NF-κB and MAPK pathway in this process.Methods:Adult male Wistar rats were randomly assigned into four groups: control group(C group),control +sevoflurane group(CS group),PAH group(M group)and PAH+sevoflurane group(MS group).Rats in MCT group received one dose peritoneal injection of MCT(60 mg/kg).Rats in CS group and MS group were treated with 1.5 minimum alveolar concentrations(MAC)sevoflurane for 1 hour twice a week for two weeks after MCT injection until 6 weeks.PAH status and cardiac function were assessed by echocardiography weekly,and the body weights(BW)were monitored every week.At the end of the study,rats hearts tissues were collected,morphological changes were observed and Fulton’s index was calculated;lung slices from right upper lobe and RV slices in different groups were used to do the histological examination and observed by light microscopy;the expression levels of IL-6 and TNF-α in lung and RV sections were detected by immunohistochemistry;The changes in oxidative indicators,including MDA,SOD and GSH-Px were measured using corresponding commercial kits;the expression levels of P65、p-P65、IκBα、p-IκBα、ERK1/2、MAPK P38、p-ERK1/2、p-MAPK P38 in RV tissue samples were determined by western blot.Results:Animals injected with MCT presented with pulmonary vascular remodeling,RVH,increased Fulton’s index(P<0.01)and increased incidence of RVF(P<0.05),while sevoflurane inhalation increases cardiac output(P<0.05)and decrease the incidence of RVF(P<0.05);The ultrasonic results showed that MCT induced rats RVEDD(the right ventricular end-diastolic dimension),RVWTd(right ventricular wall thickness in diastole),IVSd(intraventricular septum in diastole)and PAID(Pulmonary arterial internal dimension)increased(P<0.05),PV(maximal velocity of pulmonic valve)decreased(P<0.05),however,sevoflurane inhalation significantly improved these ultrasound indicators(P<0.05);For the evaluation of pathological damage,lung tissue samples from MCT group showed obvious structural disorder,inflammatory cells aggregation,small pulmonary arterial(vascular external diameter 50-150 um)wall thickness(WT%)and vascular wall area(WA%)increased(P<0.01),and RV sections in MCT group showed cardiomyocyte cross-sectional area increased (P<0.01);Masson Trichrome showed that the degree of fibrosis of RV tissues increased significantly;while inhalation of sevoflurane could attenuate these pathological damages(P<0.01);In addition,according to the immunohistochemical results,the levels of IL-6 and TNF-α in both lung and RV sections in MCT group were increased(P<0.05),and sevoflurane could improve such changes caused by MCT(P<0.05);sevoflurane also decreased MDA level,and increased SOD and GSH-Px activity(P<0.01);Furthermore,the levels of the key proteins p-P65 、p-IκBα 、 p-ERK1/2 and p-MAPK P38 indicated that the activities of NF-κB and MAPK pathways in RV tissues of rats in MCT group were increased(P<0.01),however,the levels of these proteins were significant decrease in the MCT+sevoflurane group(P<0.01).Conclusion:In summary,the present data suggest that NF-κB and MAPK signaling pathways were involved in the pathogenesis of experimental PAH.And 1.5 MAC sevoflurane inhalation can improve pulmonary vascular remodeling,RVH,and delay their progression towards RVF,this effect is likely due to the down-regulation of related inflammatory mediators such as IL-6 and TNF-α,reduced level of oxidative stress and the inhibition of NF-κB and MAPK signaling pathways.By exploring these pathways,we hope to provide ideas for perioperative anesthesia management and protection of pulmonaty function and right heart function in PAH patients.